Phillip Melton | Curtin University, Perth (original) (raw)

Papers by Phillip Melton

Phenotypic heterogeneity is a major barrier to understanding the genetic architecture underlying ... more Phenotypic heterogeneity is a major barrier to understanding the genetic architecture underlying schizophrenia. Incorporating endophenotypes is one way to reduce het-erogeneity and facilitate more powerful genetic analysis. Candidate endophenotypes require systematic assessment against endophenotype criteria, and a ranking of their potential utility for genetic analysis. In this study we assess 20 cognitive and personality measures in a sample of 127 families with at least 2 cases of schizophrenia per family (n = 535) plus a set of 30 control families (n = 121) against 4 endophenotype criteria: (a) be associated with the illness but not be a part of its diagnosis, (b) be heritable, (c) co-segregate with the illness in families, and (d) be found in unaffected relatives at a higher rate than in the general population. The endophenotype ranking score (endopheno-type ranking variable [ERV]) was used to rank candidate endophenotypes based on their heritability and genetic correlation with schizophrenia. Finally, we used factor analysis to explore latent factors underlying the cognitive and personality measures. Evidence for personality measures as endophenotypes was at least equivalent to that of the cog-nitive measures. Factor analysis indicated that personality and cognitive traits contribute to independent latent dimensions. The results suggest for this first time that a number of cognitive and personality measures are independent and informative endophenotypes. Use of these endophenotypes in genetic studies will likely improve power and facilitate novel aetiological insights.

Human Molecular Genetics, 2017

Pre-pregnancy maternal obesity is associated with adverse offspring outcomes at birth and later i... more Pre-pregnancy maternal obesity is associated with adverse offspring outcomes at birth and later in life. Individual studies have shown that epigenetic modifications such as DNA methylation could contribute.
Within the Pregnancy and Childhood Epigenetics (PACE) Consortium, we meta-analysed the
association between pre-pregnancy maternal BMI and methylation at over 450,000 sites in newborn blood DNA, across 19 cohorts (9,340 mother-newborn pairs). We attempted to infer
causality by comparing effects of maternal versus paternal BMI and incorporating genetic variation. In four additional cohorts (1,817 mother-child pairs), we meta-analysed the association between maternal BMI at the start of pregnancy and blood methylation in adolescents.
In newborns, maternal BMI was associated with small (<0.2% per BMI unit (1kg/m2), P < 1.06*10−7) methylation variation at 9,044 sites throughout the genome. Adjustment for estimated cell proportions greatly attenuated the number of significant CpGs to 104, including 86 sites common to the unadjusted model. At 72/86 sites, the direction of association was the same in newborns and adolescents, suggesting persistence of signals. However, we found evidence for a causal intrauterine effect of maternal BMI on newborn methylation at just 8/86 sites.
In conclusion, this well-powered analysis identified robust associations between maternal adiposity and variations in newborn blood DNA methylation, but these small effects may be better explained by genetic or lifestyle factors than a causal intrauterine mechanism. This highlights the need for large-scale collaborative approaches and the application of causal inference techniques in epigenetic epidemiology.

Experimental studies show a substantial contribution of early life environment to obesity risk th... more Experimental studies show a substantial contribution of early life environment to obesity risk through epigenetic processes. We examined inter-individual DNA methylation differences in human birth tissues associated with child's adiposity. We identified a novel association between the level of CpG methylation at birth within the promoter of the long non-coding RNA ANRIL (encoded at CDKN2A) and childhood adiposity at age 6-years. An association between ANRIL methylation and adiposity was also observed in three additional populations; in birth tissues from ethnically diverse neonates, in peripheral blood from adolescents, and in adipose tissue from adults. Additionally, CpG methylation was associated with ANRIL expression in vivo, and CpG mutagenesis in vitro inhibited ANRIL promoter activity. Furthermore, CpG methylation enhanced binding to an Estrogen Response Element within the ANRIL promoter. Our findings demonstrate that perinatal methylation at loci relevant to gene function may be a robust marker of later adiposity, providing substantial support for epigenetic processes in mediating long-term consequences of early life environment on human health.

abstract DNA methylation is the most widely studied of epigenetic mechanisms, with environmental ... more abstract DNA methylation is the most widely studied of epigenetic mechanisms, with environmental effects recorded through patterned attachments of methyl groups along the DNA that are capable of modifying gene expression without altering the DNA sequencing. The degree to which these patterns of DNA methylation are heritable, the expected range of normality across populations, and the phenotypic relevance of pattern variation remain unclear. Genes regulating metabolic pathways appear to be vulnerable to ongoing nutritional programming over the life course, as dietary nutrients are significant environmental determinants of DNA methylation, supplying both the methyl groups and energy to generate the methylation process. Here we examine methylation patterns along a region of the metabolic gene leptin (LEP). LEP's putative functions include regulation of energy homeostasis, with its signals affecting energy intake and expenditure, adipogenesis and energy storage, lipid and glucose metabolism, bone metabolism, and reproductive endocrine function. A pattern of differential methylation across CpG sites of the LEP core promoter has been previously identified; however, any consistency of pattern or its phenotypic significance is not fully elucidated among populations. Using DNA extracted from unfractionated white blood cells of peripheral blood samples, our pilot study, divided into two parts, examined the significance of variation in DNA methylation patterns along the leptin core promoter in four populations (phase 1) and used biomarkers reflecting leptin's functional process in two of those populations, western Buryat of Siberia and the Mennonite of central Kansas, to investigate the relevance of the ethnic variation identified in the DNA methylation (phase 2). LEP's core promoter region contains both the binding site for C/EBPα (CCAAT/enhancer binding protein alpha), which tempers the final step in adipocyte maturity and capacity to synthesize leptin, and the TATA motif controlling leptin synthesis. Previous studies report that increased methylation in this region is correlated to decreased gene expression, suggesting tissue-specific methylation variation at this region (Melzner et al. 2002). We hypothesized that evidence of nutritional epigenetic programming would be identified through variation in patterns of DNA methylation and that functional relevance of that variation among populations would be identified through biomarkers that reflect leptin's metabolic signals: serum leptin levels, lipoproteins of the lipid transport system, and anthropometric measures.

Over the last 35 years, researchers from the Laboratory of Biological Anthropology at the Univers... more Over the last 35 years, researchers from the Laboratory of Biological Anthropology at the University of Kansas have been working with Mennonite communities to better understand evolutionary patterns of fission-fusion in relationship to their genetic history and population structure. In this study, short tandem repeat (STR) markers from the nonrecombining region of the Y chromosome (NRY) provided increased resolution of the molecular population structure for these groups. NRY is known to be informative for determining paternal genetic ancestral patterns in recently derived human populations. Mennonites represent a branch of the Anabaptist movement that began in northern and central Europe in the 16th century and maintain a well-documented migration and genealogical history. Provided this historical information, we investigated the genetic relationship of 15 NRY STR loci within five Mennonite communities from Kansas (Goessel, Lone Tree, Garden View, and Meridian) and Nebraska (Henderson). We sought to determine if patterns of fission/fusion along familial lines persisted with paternal genetic information as evidenced through other classical genetic polymorphisms and molecular markers. NRY haplotype information was obtained for 94 individuals, and genetic variation was analyzed and compared across the five study populations and comparative Anabaptist and European populations. NRY haplogroups were assigned using a Bayesian allele frequency approach with 14 STR loci. A total of 92 NRY haplotypes were detected, with none shared across these communities. The most prevalent NRY haplogroup was R1b, which occurred in 56% of the entire sample. Eight additional NRY haplogroups (E1b1b, G2a, I1, I2, J2a1, L, Q, and R1a) were detected in smaller frequencies. Principal component analysis of NRY data, in contrast to mitochondrial DNA data, displayed no patterns of population subdivision of these congregations into communities. These NRY genetic profiles provide additional information regarding the recent migratory history of Mennonite communities and additional evidence for fission along paternal lines after migration to the United States.

Background: The incorporation of longitudinal data into genetic epidemiological studies has the p... more Background: The incorporation of longitudinal data into genetic epidemiological studies has the potential to provide valuable information regarding the effect of time on complex disease etiology. Yet, the majority of research focuses on variables collected from a single time point. This aim of this study was to test for main effects on a quantitative trait across time points using a constrained maximum-likelihood measured genotype approach. This method simultaneously accounts for all repeat measurements of a phenotype in families. We applied this method to systolic blood pressure (SBP) measurements from three time points using the Genetic Analysis Workshop 19 (GAW19) whole-genome sequence family simulated data set and 200 simulated replicates. Data consisted of 849 individuals from 20 extended Mexican American pedigrees. Comparisons were made among 3 statistical approaches: (a) constrained, where the effect of a variant or gene region on the mean trait value was constrained to be equal across all measurements; (b) unconstrained, where the variant or gene region effect was estimated separately for each time point; and (c) the average SBP measurement from three time points. These approaches were run for nine genetic variants with known effect sizes (>0.001) for SBP variability and a known gene-centric kernel (MAP4)-based test under the GAW19 simulation model across 200 replicates. Results: When compared to results using two time points, the constrained method utilizing all 3 time points increased power to detect association. Averaging SBP was equally effective when the variant has a large effect on the phenotype, but less powerful for variants with lower effect sizes. However, averaging SBP was far more effective than either the constrained or unconstrained approaches when using a gene-centric kernel-based test. Conclusion: We determined that this constrained multivariate approach improves genetic signal over the bivariate method. However, this method is still only effective in those variants that explain a moderate to large proportion of the phenotypic variance but is not as effective for gene-centric tests.

The user has requested enhancement of the downloaded file. All in-text references underlined in b... more The user has requested enhancement of the downloaded file. All in-text references underlined in blue are linked to publications on ResearchGate, letting you access and read them immediately.

The exome array assays rare-but-recurrent, likely deleterious, exonic variants and represents an ... more The exome array assays rare-but-recurrent, likely deleterious, exonic variants and represents an intermediary between single nucleotide polymorphism (SNP) arrays and sequencing for genetic association studies. Multiplex families with multiple affected individuals may be enriched for disease-associated variants of this class compared to unrelated populations. We present an exome array study of schizophrenia in 99 multiplex families (n = 341, including 118 cases) from the Western Australian Family Study of Schizophrenia (WAFSS). Compared to 55,726 individuals from the DIAGRAM sample not selected for schizophrenia, overall allele frequency of exome variants was higher in the WAFSS (P b 2.2E-16). This was pronounced in variants nominally associated (P b 0.05) with schizophrenia. Genes harbouring variants present only in WAFSS cases were enriched (FDR-corrected P = 0.05) for membership of the 'extracellular matrix (ECM) -receptor interaction' biological pathway, adding to evidence that processes affecting the composition or turnover of ECM may contribute to neuropsychiatric disease. We did not find individual variants significantly associated with schizophrenia, although like previous studies, power to detect associations of small effect size was low. Cases did not exhibit a higher burden of variants compared to their unaffected relatives and the finding of previous exome chip studies of unrelated samples that 'schizophrenia gene-sets' were enriched for case-only variants was not replicated in the WAFSS. The higher frequency of moderately rare, exonic variants in these multiplex families compared to a populationbased sample may account for some of their genetic liability to schizophrenia, and adds to evidence for a role of exome array variants from previous studies of unrelated samples. Please cite this article as: McCarthy, N.S., et al., Exome array analysis suggests an increased variant burden in families with schizophrenia, Schizophr. Res. (2016), http://dx.

Objective: Preeclampsia is a complex heterogeneous disease commonly defined by new-onset hyperten... more Objective: Preeclampsia is a complex heterogeneous disease commonly defined by new-onset hypertension and proteinuria in pregnancy. Women experiencing preeclampsia have increased risk for cardiovascular diseases (CVD) later in life. Preeclampsia and CVD share risk factors and pathophysiologic mechanisms, including dysregulated inflammation and raised blood pressure. Despite commonalities, little is known about the contribution of shared genes (pleiotropy) to these diseases. This study aimed to investigate whether genetic risk factors for hypertension or inflammation are pleiotropic by also being associated with preeclampsia.

Methods: We genotyped 122 single nucleotide polymorphisms (SNPs) in women with preeclampsia (n = 1006) and nonpreeclamptic controls (n = 816) from the Norwegian HUNT Study. SNPs were chosen on the basis of previously reported associations with either nongestational hypertension or inflammation in genome-wide association studies. The SNPs were tested for association with preeclampsia in a multiple logistic regression model.

Results: The minor (G) allele of the intronic SNP rs17367504 in the gene methylenetetrahydrofolate reductase (MTHFR) was associated with a protective effect on preeclampsia (odds ratio 0.65, 95% confidence interval 0.53-0.80) in the Norwegian cohort. This association did not replicate in an Australian preeclampsia case-control cohort (P = 0.68, odds ratio 1.05, 95% confidence interval 0.83-1.32, minor allele frequency = 0.15).

Conclusion: MTHFR is important for regulating transmethylation processes and is involved in regulation of folate metabolism. The G allele of rs17367504 has previously been shown to protect against nongestational hypertension. Our study suggests a novel association between this allele and reduced risk for preeclampsia. This is the first study associating the minor (G) allele of a SNP within the MTHFR gene with a protective effect on preeclampsia, and in doing so identifying a possible pleiotropic protective effect on preeclampsia and hypertension.

Age is well-known to be a significant factor in both disease pathology and response to treatment,... more Age is well-known to be a significant factor in both disease pathology and response to treatment, yet the molecular changes that occur with age in humans remain ill-defined. Here, using transcriptome profiling of healthy human male skin, we demonstrate that there is a period of significantly elevated, transcriptome-wide expression changes occurring predominantly in middle age. Both pre and post this period, the transcriptome appears to undergo much smaller, linear changes with increasing age. Functional analysis of the transient changes in middle age suggest a period of heightened metabolic activity and cellular damage associated with NF-kappa-B and TNF signaling pathways. Through meta-analysis we also show the presence of global, tissue independent linear transcriptome changes with age which appear to be regulated by NF-kappa-B. These results suggest that aging in human skin is associated with a critical mid-life period with widespread transcriptome changes, both preceded and proceeded by a relatively steady rate of linear change in the transcriptome. The data provides insight into molecular changes associated with normal aging and will help to better understand the increasingly important pathological changes associated with aging. Few organs are as consciously linked to aging as skin, which through loss of elasticity and formation of wrinkles serves as a stark visual reminder of the process. However, age related changes in the skin are more than just cosmetic , with decline in function manifested by inefficiencies in physiological processes including wound healing and thermoregulation 1. Further the extent of functional decline in internal tissues can be estimated through sampling of the skin 2. Despite this, much remains unknown regarding the changes in the transcriptome with aging in the skin, and whether the changes observed in other organs are indicative of a universal or tissue specific aging process. Numerous evolutionary theories of aging have attempted to explain how a universal aging process would occur. Two such theories are those of antagonistic pleiotropy and the disposable soma, which suggest an inverse relationship between reproduction and aging 3. These theories hypothesize that aging occurs as a result of a " trade-off ". Consistent with a link between reproduction and aging are observations in model organisms that a lower rate of reproduction slows down aging. Genetically manipulated long-lived model organisms display decreased fecundity, while lifespan also increases with ablation of their germ-line or removal of the entire reproductive system 4,5. Despite this, there is little evidence of a relationship between reproduction and aging in humans. Indeed, studies of human aging have largely ignored the possibility that discrete time periods, such as the reproductive period, may modulate the aging process.

Background: Longitudinal phenotypic data provides a rich potential resource for genetic studies w... more Background: Longitudinal phenotypic data provides a rich potential resource for genetic studies which may allow for greater understanding of variants and their covariates over time. Herein, we review 3 longitudinal analytical approaches from the Genetic Analysis Workshop 19 (GAW19). These contributions investigated both genome-wide association (GWA) and whole genome sequence (WGS) data from odd numbered chromosomes on up to 4 time points for blood pressure–related phenotypes. The statistical models used included generalized estimating equations (GEEs), latent class growth modeling (LCGM), linear mixed-effect (LME), and variance components (VC). The goal of these analyses was to test statistical approaches that use repeat measurements to increase genetic signal for variant identification.

… journal of physical …, Jan 1, 2007

We examined mitochondrial DNA (mtDNA) haplogroup and haplotype diversity in 188 individuals from ... more We examined mitochondrial DNA (mtDNA) haplogroup and haplotype diversity in 188 individuals from three Chibchan (Kogi, Arsario, and Ijka) populations and one Arawak (Wayuú) group from northeast Colombia to determine the biological relationship between lower Central American and northern South American Chibchan speakers. mtDNA haplogroups were obtained for all individuals and mtDNA HVS-I sequence data were obtained for 110 samples. Resulting sequence data were compared to 16 other Caribbean, South, and Central American populations using diversity measures, neutrality test statistics, sudden and spatial mismatch models, intermatch distributions, phylogenetic networks, and a multidimensional scaling plot. Our results demonstrate the existence of a shared maternal genetic structure between Central American Chibchan, Mayan populations and northern South American Chibchan-speakers. Additionally, these results suggest an expansion of Chibchan-speakers into South America associated with a shift in subsistence strategies because of changing ecological conditions that occurred in the region between 10,000-14,000 years before present. (c) 2007 Wiley-Liss, Inc.

Mitochondrial DNA of Yakuts has been compared to those of other Asian populations that belong to ... more Mitochondrial DNA of Yakuts has been compared to those of other Asian populations that belong to the Turkic, Mongolic, and Manchu-Tungusic linguistic groups. Haplogroups C and D proved to be the most frequent ones in Yakuts. In contrast to other Asian populations, subcluster D5a is major in Yakuts. The results have demonstrated that Yakuts are close to Tuvinians and Altaians in maternal lineage.

Background The Asian origin of Native Americans is largely accepted. However uncertainties persi... more Background
The Asian origin of Native Americans is largely accepted. However uncertainties persist regarding the source population(s) within Asia, the divergence and arrival time(s) of the founder groups, the number of expansion events, and migration routes into the New World. mtDNA data, presented over the past two decades, have been used to suggest a single-migration model for which the Beringian land mass plays an important role.

Results
In our analysis of 568 mitochondrial genomes, the coalescent age estimates of shared roots between Native American and Siberian-Asian lineages, calculated using two different mutation rates, are A4 (27.5+/-6.8 kya/22.7+/-7.4 kya), C1 (21.4+/-2.7 kya/16.4+/-1.5 kya), C4 (21.0+/-4.6 kya/20.0+/-6.4 kya), and D4e1 (24.1+/-9.0 kya/17.9+/-10.0 kya). The coalescent age estimates of pan-American haplogroups calculated using the same two mutation rates (A2: 19.5+/-1.3 kya/16.1+/-1.5 kya, B2: 20.8+/-2.0 kya/18.1+/-2.4 kya, C1: 21.4+/-2.7 kya/16.4+/-1.5 kya and D1: 17.2+/-2.0 kya/14.9+/-2.2 kya) and estimates of population expansions within America (~21-16 kya), support the pre-Clovis occupation of the New World. The phylogeography of sublineages within American haplogroups A2, B2, D1 and the C1b, C1c andC1d subhaplogroups of C1 are complex and largely specific to geographical North, Central and South America. However some sub-branches (B2b, C1b, C1c, C1d and D1f) already existed in American founder haplogroups before expansion into the America.

Conclusions
Our results suggest that Native American founders diverged from their Siberian-Asian progenitors sometime during the last glacial maximum (LGM) and expanded into America soon after the LGM peak (~20-16 kya). The phylogeography of haplogroup C1 suggest that this American founder haplogroup differentiated in Siberia-Asia. The situation is less clear for haplogroup B2, however haplogroups A2 and D1 may have differentiated soon after the Native American founders divergence. A moderate population bottle neck in American founder populations just before the expansion most plausibly resulted in few founder types in America. The similar estimates of the diversity indices and Bayesian skyline analysis in North America, Central America and South America suggest almost simultaneous (~ 2.0 ky from South to North America) colonization of these geographical regions with rapid population expansion differentiating into more or less regional branches across the pan-American haplogroups.

The joint analysis of multiple disease phenotypes aims to increase statistical power and potentia... more The joint analysis of multiple disease phenotypes aims to increase statistical power and potentially identify pleiotropic genes involved in the biological development of common chronic diseases. As next-generation sequencing data become more common, it will be important to consider ways to maximize the ability to detect rare variants within the human genome. The two exome sequence data sets provided for analysis at Genetic Analysis Workshop 17 (GAW17) offered three quantitative phenotypes related to disease status in 200 simulated replicates for both families and unrelated individuals. Participants in Group 10 addressed the challenges and potential uses of next-generation sequencing data to identify causal variants through a broad range of statistical methods. These methods included investigating multiple phenotypes either through data reduction or joint methods, using family or unrelated individuals, and reducing the dimensionality inherent in these data. Most of the research teams regarded the use of multiple phenotypes as a means of increasing analytical power and as a way to clarify the biology of complex disease. Three major observations were gleaned from these Group 10 contributions. First, family and unrelated case-control samples are suited to finding different types of variants. In addition, collapsing either phenotypes or genotypes can reduce the dimensionality of the data and alleviate some of the problems of multiple testing. Finally, we were able to demonstrate in certain cases that performing a joint analysis of disease status and a quantitative trait can improve statistical power.

American journal of human biology : the official journal of the Human Biology Council, 2013

Objective: This research examines the coevolution of languages and uniparental genetic marker (mi... more Objective: This research examines the coevolution of languages and uniparental genetic marker (mitochondrial DNA [mtDNA] and nonrecombining Y-chromosome [NRY]) variation within five Lower Central American (Rama, Chorotega, Mal eku, Zapat on-Huetar, and Abrojo-Guaym ı) Amerindian groups. This pattern occurred since European contact.

Genetic epidemiology, 2014

The analysis of whole-genome sequence (WGS) data using longitudinal phenotypes offers a potential... more The analysis of whole-genome sequence (WGS) data using longitudinal phenotypes offers a potentially rich resource for the examination of the genetic variants and their covariates that affect complex phenotypes over time. We summarize eight contributions to the Genetic Analysis Workshop 18, which applied a diverse array of statistical genetic methods to analyze WGS data in combination with data from genome-wide association studies (GWAS) from up to four different time points on blood pressure phenotypes. The common goal of these analyses was to develop and apply appropriate methods that utilize longitudinal repeated measures to potentially increase the analytic efficiency of WGS and GWAS data. These diverse methods can be grouped into two categories, based on the way they model dependence structures: (1) linear mixed-effects (LME) models, where the random effect terms in the linear models are used to capture the dependence structures; and (2) variance-components models, where the dependence structures are constructed directly based on multiple components of variance-covariance matrices for the multivariate Gaussian responses. Despite the heterogeneous nature of these analytical methods, the group came to the following conclusions: (1) the use of repeat measurements can gain power to identify variants associated with the phenotype; (2) the inclusion of family data may correct genotyping errors and allow for more accurate detection of rare variants than using unrelated individuals only; and (3) fitting mixed-effects and variance-components models for longitudinal data presents computational challenges. The challenges and computational burden demanded by WGS data were addressed in the eight contributions.

American Journal of Human Biology, Jan 2011

"Objective: To identify genetic variation influencing serum bilirubin levels in American Indians,... more "Objective: To identify genetic variation influencing serum bilirubin levels in American Indians, we performed genome-wide screening and association analyses in the Strong Heart Family Study. Bilirubin is an endogenous antioxidant that has demonstrated an inverse relationship with cardiovascular disease. Genetic variation within the promoter region of uridine diphosphate glucuronosyltransferase (UGT1A1) on chromosome 2q has been associated with elevated serum bilirubin levels in European populations. However, no study has investigated the UGT1A1 promoter in American Indians.

Methods: Statistical analyses were carried out with 3,484 participants aged 14 to 93 years recruited from three geographic areas in the United States; Arizona, Oklahoma, and North and South Dakota.

Results: Variance components linkage analysis detected a quantitative trait locus (QTL) for bilirubin on chromosome 2q in the combined centers (LOD = 6.61, P = 4.24 × 10−6) and in Oklahoma (LOD = 5.65, P = 4.57 24 × 10−5). Genetic association of the UGT1A1 promoter polymorphism was significant for all geographic locations. After adjustment using conditional linkage for UGT1A1 promoter variance, the linkage signal dropped to 1.10 in the combined sample and to 3.32 (P = 0.02) in Oklahoma, indicating this polymorphism is not completely responsible for the linkage signal in American Indians. We also detected suggestive linkage signals in the Dakotas on chromosome 10p12 (LOD = 2.18) and in the combined centers (LOD = 2.24) on chromosome 10q21.

Conclusions: Replication of a serum bilirubin QTL on chromosome 2q in American Indians implicates UGT1A1 but further genotyping is warranted to identify additional causative polymorphisms. Evidence also supports a potential novel locus for bilirubin on chromosome 10.
"

Background Preeclampsia (PE) is a serious hypertensive pregnancy disorder with a significant gen... more Background

Preeclampsia (PE) is a serious hypertensive pregnancy disorder with a significant genetic component. Numerous genetic studies, including our own, have yielded many susceptibility genes from distinct functional groups. Additionally, transcriptome profiling of tissues at the maternal-fetal interface has likewise yielded many differentially expressed genes. Often there is little overlap between these two approaches, although genes identified in both approaches are significantly associated with PE. We have thus taken a novel integrative bioinformatics approach of analysing pathways common to the susceptibility genes and the PE transcriptome.

Methods

Using Illumina Human Ht12v4 and Wg6v3 BeadChips, transcriptome profiling was conducted on n = 65 normotensive and n = 60 PE decidua basalis tissues collected at delivery. The R software package libraries lumi and limma were used to preprocess transcript data for pathway analysis. Pathways were analysed and constructed using Pathway Studio. We examined ten candidate genes, which are from these functional groups: activin/inhibin signalling—ACVR1, ACVR1C, ACVR2A, INHA, INHBB; structural components—COL4A1, COL4A2 and M1 family aminopeptidases—ERAP1, ERAP2 and LNPEP.

Results/Conclusion

Major common regulators/targets of these susceptibility genes identified were AGT, IFNG, IL6, INHBA, SERPINE1, TGFB1 and VEGFA. The top two categories of pathways associated with the susceptibility genes, which were significantly altered in the PE decidual transcriptome, were apoptosis and cell signaling (p < 0.001). Thus, susceptibility genes from distinct functional groups share similar downstream pathways through common regulators/targets, some of which are altered in PE. This study contributes to a better understanding of how susceptibility genes may interact in the development of PE. With this knowledge, more targeted functional analyses of PE susceptibility genes in these key pathways can be performed to examine their contributions to the pathogenesis and severity of PE.

Phenotypic heterogeneity is a major barrier to understanding the genetic architecture underlying ... more Phenotypic heterogeneity is a major barrier to understanding the genetic architecture underlying schizophrenia. Incorporating endophenotypes is one way to reduce het-erogeneity and facilitate more powerful genetic analysis. Candidate endophenotypes require systematic assessment against endophenotype criteria, and a ranking of their potential utility for genetic analysis. In this study we assess 20 cognitive and personality measures in a sample of 127 families with at least 2 cases of schizophrenia per family (n = 535) plus a set of 30 control families (n = 121) against 4 endophenotype criteria: (a) be associated with the illness but not be a part of its diagnosis, (b) be heritable, (c) co-segregate with the illness in families, and (d) be found in unaffected relatives at a higher rate than in the general population. The endophenotype ranking score (endopheno-type ranking variable [ERV]) was used to rank candidate endophenotypes based on their heritability and genetic correlation with schizophrenia. Finally, we used factor analysis to explore latent factors underlying the cognitive and personality measures. Evidence for personality measures as endophenotypes was at least equivalent to that of the cog-nitive measures. Factor analysis indicated that personality and cognitive traits contribute to independent latent dimensions. The results suggest for this first time that a number of cognitive and personality measures are independent and informative endophenotypes. Use of these endophenotypes in genetic studies will likely improve power and facilitate novel aetiological insights.

Human Molecular Genetics, 2017

Pre-pregnancy maternal obesity is associated with adverse offspring outcomes at birth and later i... more Pre-pregnancy maternal obesity is associated with adverse offspring outcomes at birth and later in life. Individual studies have shown that epigenetic modifications such as DNA methylation could contribute.
Within the Pregnancy and Childhood Epigenetics (PACE) Consortium, we meta-analysed the
association between pre-pregnancy maternal BMI and methylation at over 450,000 sites in newborn blood DNA, across 19 cohorts (9,340 mother-newborn pairs). We attempted to infer
causality by comparing effects of maternal versus paternal BMI and incorporating genetic variation. In four additional cohorts (1,817 mother-child pairs), we meta-analysed the association between maternal BMI at the start of pregnancy and blood methylation in adolescents.
In newborns, maternal BMI was associated with small (<0.2% per BMI unit (1kg/m2), P < 1.06*10−7) methylation variation at 9,044 sites throughout the genome. Adjustment for estimated cell proportions greatly attenuated the number of significant CpGs to 104, including 86 sites common to the unadjusted model. At 72/86 sites, the direction of association was the same in newborns and adolescents, suggesting persistence of signals. However, we found evidence for a causal intrauterine effect of maternal BMI on newborn methylation at just 8/86 sites.
In conclusion, this well-powered analysis identified robust associations between maternal adiposity and variations in newborn blood DNA methylation, but these small effects may be better explained by genetic or lifestyle factors than a causal intrauterine mechanism. This highlights the need for large-scale collaborative approaches and the application of causal inference techniques in epigenetic epidemiology.

Experimental studies show a substantial contribution of early life environment to obesity risk th... more Experimental studies show a substantial contribution of early life environment to obesity risk through epigenetic processes. We examined inter-individual DNA methylation differences in human birth tissues associated with child's adiposity. We identified a novel association between the level of CpG methylation at birth within the promoter of the long non-coding RNA ANRIL (encoded at CDKN2A) and childhood adiposity at age 6-years. An association between ANRIL methylation and adiposity was also observed in three additional populations; in birth tissues from ethnically diverse neonates, in peripheral blood from adolescents, and in adipose tissue from adults. Additionally, CpG methylation was associated with ANRIL expression in vivo, and CpG mutagenesis in vitro inhibited ANRIL promoter activity. Furthermore, CpG methylation enhanced binding to an Estrogen Response Element within the ANRIL promoter. Our findings demonstrate that perinatal methylation at loci relevant to gene function may be a robust marker of later adiposity, providing substantial support for epigenetic processes in mediating long-term consequences of early life environment on human health.

abstract DNA methylation is the most widely studied of epigenetic mechanisms, with environmental ... more abstract DNA methylation is the most widely studied of epigenetic mechanisms, with environmental effects recorded through patterned attachments of methyl groups along the DNA that are capable of modifying gene expression without altering the DNA sequencing. The degree to which these patterns of DNA methylation are heritable, the expected range of normality across populations, and the phenotypic relevance of pattern variation remain unclear. Genes regulating metabolic pathways appear to be vulnerable to ongoing nutritional programming over the life course, as dietary nutrients are significant environmental determinants of DNA methylation, supplying both the methyl groups and energy to generate the methylation process. Here we examine methylation patterns along a region of the metabolic gene leptin (LEP). LEP's putative functions include regulation of energy homeostasis, with its signals affecting energy intake and expenditure, adipogenesis and energy storage, lipid and glucose metabolism, bone metabolism, and reproductive endocrine function. A pattern of differential methylation across CpG sites of the LEP core promoter has been previously identified; however, any consistency of pattern or its phenotypic significance is not fully elucidated among populations. Using DNA extracted from unfractionated white blood cells of peripheral blood samples, our pilot study, divided into two parts, examined the significance of variation in DNA methylation patterns along the leptin core promoter in four populations (phase 1) and used biomarkers reflecting leptin's functional process in two of those populations, western Buryat of Siberia and the Mennonite of central Kansas, to investigate the relevance of the ethnic variation identified in the DNA methylation (phase 2). LEP's core promoter region contains both the binding site for C/EBPα (CCAAT/enhancer binding protein alpha), which tempers the final step in adipocyte maturity and capacity to synthesize leptin, and the TATA motif controlling leptin synthesis. Previous studies report that increased methylation in this region is correlated to decreased gene expression, suggesting tissue-specific methylation variation at this region (Melzner et al. 2002). We hypothesized that evidence of nutritional epigenetic programming would be identified through variation in patterns of DNA methylation and that functional relevance of that variation among populations would be identified through biomarkers that reflect leptin's metabolic signals: serum leptin levels, lipoproteins of the lipid transport system, and anthropometric measures.

Over the last 35 years, researchers from the Laboratory of Biological Anthropology at the Univers... more Over the last 35 years, researchers from the Laboratory of Biological Anthropology at the University of Kansas have been working with Mennonite communities to better understand evolutionary patterns of fission-fusion in relationship to their genetic history and population structure. In this study, short tandem repeat (STR) markers from the nonrecombining region of the Y chromosome (NRY) provided increased resolution of the molecular population structure for these groups. NRY is known to be informative for determining paternal genetic ancestral patterns in recently derived human populations. Mennonites represent a branch of the Anabaptist movement that began in northern and central Europe in the 16th century and maintain a well-documented migration and genealogical history. Provided this historical information, we investigated the genetic relationship of 15 NRY STR loci within five Mennonite communities from Kansas (Goessel, Lone Tree, Garden View, and Meridian) and Nebraska (Henderson). We sought to determine if patterns of fission/fusion along familial lines persisted with paternal genetic information as evidenced through other classical genetic polymorphisms and molecular markers. NRY haplotype information was obtained for 94 individuals, and genetic variation was analyzed and compared across the five study populations and comparative Anabaptist and European populations. NRY haplogroups were assigned using a Bayesian allele frequency approach with 14 STR loci. A total of 92 NRY haplotypes were detected, with none shared across these communities. The most prevalent NRY haplogroup was R1b, which occurred in 56% of the entire sample. Eight additional NRY haplogroups (E1b1b, G2a, I1, I2, J2a1, L, Q, and R1a) were detected in smaller frequencies. Principal component analysis of NRY data, in contrast to mitochondrial DNA data, displayed no patterns of population subdivision of these congregations into communities. These NRY genetic profiles provide additional information regarding the recent migratory history of Mennonite communities and additional evidence for fission along paternal lines after migration to the United States.

Background: The incorporation of longitudinal data into genetic epidemiological studies has the p... more Background: The incorporation of longitudinal data into genetic epidemiological studies has the potential to provide valuable information regarding the effect of time on complex disease etiology. Yet, the majority of research focuses on variables collected from a single time point. This aim of this study was to test for main effects on a quantitative trait across time points using a constrained maximum-likelihood measured genotype approach. This method simultaneously accounts for all repeat measurements of a phenotype in families. We applied this method to systolic blood pressure (SBP) measurements from three time points using the Genetic Analysis Workshop 19 (GAW19) whole-genome sequence family simulated data set and 200 simulated replicates. Data consisted of 849 individuals from 20 extended Mexican American pedigrees. Comparisons were made among 3 statistical approaches: (a) constrained, where the effect of a variant or gene region on the mean trait value was constrained to be equal across all measurements; (b) unconstrained, where the variant or gene region effect was estimated separately for each time point; and (c) the average SBP measurement from three time points. These approaches were run for nine genetic variants with known effect sizes (>0.001) for SBP variability and a known gene-centric kernel (MAP4)-based test under the GAW19 simulation model across 200 replicates. Results: When compared to results using two time points, the constrained method utilizing all 3 time points increased power to detect association. Averaging SBP was equally effective when the variant has a large effect on the phenotype, but less powerful for variants with lower effect sizes. However, averaging SBP was far more effective than either the constrained or unconstrained approaches when using a gene-centric kernel-based test. Conclusion: We determined that this constrained multivariate approach improves genetic signal over the bivariate method. However, this method is still only effective in those variants that explain a moderate to large proportion of the phenotypic variance but is not as effective for gene-centric tests.

The user has requested enhancement of the downloaded file. All in-text references underlined in b... more The user has requested enhancement of the downloaded file. All in-text references underlined in blue are linked to publications on ResearchGate, letting you access and read them immediately.

The exome array assays rare-but-recurrent, likely deleterious, exonic variants and represents an ... more The exome array assays rare-but-recurrent, likely deleterious, exonic variants and represents an intermediary between single nucleotide polymorphism (SNP) arrays and sequencing for genetic association studies. Multiplex families with multiple affected individuals may be enriched for disease-associated variants of this class compared to unrelated populations. We present an exome array study of schizophrenia in 99 multiplex families (n = 341, including 118 cases) from the Western Australian Family Study of Schizophrenia (WAFSS). Compared to 55,726 individuals from the DIAGRAM sample not selected for schizophrenia, overall allele frequency of exome variants was higher in the WAFSS (P b 2.2E-16). This was pronounced in variants nominally associated (P b 0.05) with schizophrenia. Genes harbouring variants present only in WAFSS cases were enriched (FDR-corrected P = 0.05) for membership of the 'extracellular matrix (ECM) -receptor interaction' biological pathway, adding to evidence that processes affecting the composition or turnover of ECM may contribute to neuropsychiatric disease. We did not find individual variants significantly associated with schizophrenia, although like previous studies, power to detect associations of small effect size was low. Cases did not exhibit a higher burden of variants compared to their unaffected relatives and the finding of previous exome chip studies of unrelated samples that 'schizophrenia gene-sets' were enriched for case-only variants was not replicated in the WAFSS. The higher frequency of moderately rare, exonic variants in these multiplex families compared to a populationbased sample may account for some of their genetic liability to schizophrenia, and adds to evidence for a role of exome array variants from previous studies of unrelated samples. Please cite this article as: McCarthy, N.S., et al., Exome array analysis suggests an increased variant burden in families with schizophrenia, Schizophr. Res. (2016), http://dx.

Objective: Preeclampsia is a complex heterogeneous disease commonly defined by new-onset hyperten... more Objective: Preeclampsia is a complex heterogeneous disease commonly defined by new-onset hypertension and proteinuria in pregnancy. Women experiencing preeclampsia have increased risk for cardiovascular diseases (CVD) later in life. Preeclampsia and CVD share risk factors and pathophysiologic mechanisms, including dysregulated inflammation and raised blood pressure. Despite commonalities, little is known about the contribution of shared genes (pleiotropy) to these diseases. This study aimed to investigate whether genetic risk factors for hypertension or inflammation are pleiotropic by also being associated with preeclampsia.

Methods: We genotyped 122 single nucleotide polymorphisms (SNPs) in women with preeclampsia (n = 1006) and nonpreeclamptic controls (n = 816) from the Norwegian HUNT Study. SNPs were chosen on the basis of previously reported associations with either nongestational hypertension or inflammation in genome-wide association studies. The SNPs were tested for association with preeclampsia in a multiple logistic regression model.

Results: The minor (G) allele of the intronic SNP rs17367504 in the gene methylenetetrahydrofolate reductase (MTHFR) was associated with a protective effect on preeclampsia (odds ratio 0.65, 95% confidence interval 0.53-0.80) in the Norwegian cohort. This association did not replicate in an Australian preeclampsia case-control cohort (P = 0.68, odds ratio 1.05, 95% confidence interval 0.83-1.32, minor allele frequency = 0.15).

Conclusion: MTHFR is important for regulating transmethylation processes and is involved in regulation of folate metabolism. The G allele of rs17367504 has previously been shown to protect against nongestational hypertension. Our study suggests a novel association between this allele and reduced risk for preeclampsia. This is the first study associating the minor (G) allele of a SNP within the MTHFR gene with a protective effect on preeclampsia, and in doing so identifying a possible pleiotropic protective effect on preeclampsia and hypertension.

Age is well-known to be a significant factor in both disease pathology and response to treatment,... more Age is well-known to be a significant factor in both disease pathology and response to treatment, yet the molecular changes that occur with age in humans remain ill-defined. Here, using transcriptome profiling of healthy human male skin, we demonstrate that there is a period of significantly elevated, transcriptome-wide expression changes occurring predominantly in middle age. Both pre and post this period, the transcriptome appears to undergo much smaller, linear changes with increasing age. Functional analysis of the transient changes in middle age suggest a period of heightened metabolic activity and cellular damage associated with NF-kappa-B and TNF signaling pathways. Through meta-analysis we also show the presence of global, tissue independent linear transcriptome changes with age which appear to be regulated by NF-kappa-B. These results suggest that aging in human skin is associated with a critical mid-life period with widespread transcriptome changes, both preceded and proceeded by a relatively steady rate of linear change in the transcriptome. The data provides insight into molecular changes associated with normal aging and will help to better understand the increasingly important pathological changes associated with aging. Few organs are as consciously linked to aging as skin, which through loss of elasticity and formation of wrinkles serves as a stark visual reminder of the process. However, age related changes in the skin are more than just cosmetic , with decline in function manifested by inefficiencies in physiological processes including wound healing and thermoregulation 1. Further the extent of functional decline in internal tissues can be estimated through sampling of the skin 2. Despite this, much remains unknown regarding the changes in the transcriptome with aging in the skin, and whether the changes observed in other organs are indicative of a universal or tissue specific aging process. Numerous evolutionary theories of aging have attempted to explain how a universal aging process would occur. Two such theories are those of antagonistic pleiotropy and the disposable soma, which suggest an inverse relationship between reproduction and aging 3. These theories hypothesize that aging occurs as a result of a " trade-off ". Consistent with a link between reproduction and aging are observations in model organisms that a lower rate of reproduction slows down aging. Genetically manipulated long-lived model organisms display decreased fecundity, while lifespan also increases with ablation of their germ-line or removal of the entire reproductive system 4,5. Despite this, there is little evidence of a relationship between reproduction and aging in humans. Indeed, studies of human aging have largely ignored the possibility that discrete time periods, such as the reproductive period, may modulate the aging process.

Background: Longitudinal phenotypic data provides a rich potential resource for genetic studies w... more Background: Longitudinal phenotypic data provides a rich potential resource for genetic studies which may allow for greater understanding of variants and their covariates over time. Herein, we review 3 longitudinal analytical approaches from the Genetic Analysis Workshop 19 (GAW19). These contributions investigated both genome-wide association (GWA) and whole genome sequence (WGS) data from odd numbered chromosomes on up to 4 time points for blood pressure–related phenotypes. The statistical models used included generalized estimating equations (GEEs), latent class growth modeling (LCGM), linear mixed-effect (LME), and variance components (VC). The goal of these analyses was to test statistical approaches that use repeat measurements to increase genetic signal for variant identification.

… journal of physical …, Jan 1, 2007

We examined mitochondrial DNA (mtDNA) haplogroup and haplotype diversity in 188 individuals from ... more We examined mitochondrial DNA (mtDNA) haplogroup and haplotype diversity in 188 individuals from three Chibchan (Kogi, Arsario, and Ijka) populations and one Arawak (Wayuú) group from northeast Colombia to determine the biological relationship between lower Central American and northern South American Chibchan speakers. mtDNA haplogroups were obtained for all individuals and mtDNA HVS-I sequence data were obtained for 110 samples. Resulting sequence data were compared to 16 other Caribbean, South, and Central American populations using diversity measures, neutrality test statistics, sudden and spatial mismatch models, intermatch distributions, phylogenetic networks, and a multidimensional scaling plot. Our results demonstrate the existence of a shared maternal genetic structure between Central American Chibchan, Mayan populations and northern South American Chibchan-speakers. Additionally, these results suggest an expansion of Chibchan-speakers into South America associated with a shift in subsistence strategies because of changing ecological conditions that occurred in the region between 10,000-14,000 years before present. (c) 2007 Wiley-Liss, Inc.

Mitochondrial DNA of Yakuts has been compared to those of other Asian populations that belong to ... more Mitochondrial DNA of Yakuts has been compared to those of other Asian populations that belong to the Turkic, Mongolic, and Manchu-Tungusic linguistic groups. Haplogroups C and D proved to be the most frequent ones in Yakuts. In contrast to other Asian populations, subcluster D5a is major in Yakuts. The results have demonstrated that Yakuts are close to Tuvinians and Altaians in maternal lineage.

Background The Asian origin of Native Americans is largely accepted. However uncertainties persi... more Background
The Asian origin of Native Americans is largely accepted. However uncertainties persist regarding the source population(s) within Asia, the divergence and arrival time(s) of the founder groups, the number of expansion events, and migration routes into the New World. mtDNA data, presented over the past two decades, have been used to suggest a single-migration model for which the Beringian land mass plays an important role.

Results
In our analysis of 568 mitochondrial genomes, the coalescent age estimates of shared roots between Native American and Siberian-Asian lineages, calculated using two different mutation rates, are A4 (27.5+/-6.8 kya/22.7+/-7.4 kya), C1 (21.4+/-2.7 kya/16.4+/-1.5 kya), C4 (21.0+/-4.6 kya/20.0+/-6.4 kya), and D4e1 (24.1+/-9.0 kya/17.9+/-10.0 kya). The coalescent age estimates of pan-American haplogroups calculated using the same two mutation rates (A2: 19.5+/-1.3 kya/16.1+/-1.5 kya, B2: 20.8+/-2.0 kya/18.1+/-2.4 kya, C1: 21.4+/-2.7 kya/16.4+/-1.5 kya and D1: 17.2+/-2.0 kya/14.9+/-2.2 kya) and estimates of population expansions within America (~21-16 kya), support the pre-Clovis occupation of the New World. The phylogeography of sublineages within American haplogroups A2, B2, D1 and the C1b, C1c andC1d subhaplogroups of C1 are complex and largely specific to geographical North, Central and South America. However some sub-branches (B2b, C1b, C1c, C1d and D1f) already existed in American founder haplogroups before expansion into the America.

Conclusions
Our results suggest that Native American founders diverged from their Siberian-Asian progenitors sometime during the last glacial maximum (LGM) and expanded into America soon after the LGM peak (~20-16 kya). The phylogeography of haplogroup C1 suggest that this American founder haplogroup differentiated in Siberia-Asia. The situation is less clear for haplogroup B2, however haplogroups A2 and D1 may have differentiated soon after the Native American founders divergence. A moderate population bottle neck in American founder populations just before the expansion most plausibly resulted in few founder types in America. The similar estimates of the diversity indices and Bayesian skyline analysis in North America, Central America and South America suggest almost simultaneous (~ 2.0 ky from South to North America) colonization of these geographical regions with rapid population expansion differentiating into more or less regional branches across the pan-American haplogroups.

The joint analysis of multiple disease phenotypes aims to increase statistical power and potentia... more The joint analysis of multiple disease phenotypes aims to increase statistical power and potentially identify pleiotropic genes involved in the biological development of common chronic diseases. As next-generation sequencing data become more common, it will be important to consider ways to maximize the ability to detect rare variants within the human genome. The two exome sequence data sets provided for analysis at Genetic Analysis Workshop 17 (GAW17) offered three quantitative phenotypes related to disease status in 200 simulated replicates for both families and unrelated individuals. Participants in Group 10 addressed the challenges and potential uses of next-generation sequencing data to identify causal variants through a broad range of statistical methods. These methods included investigating multiple phenotypes either through data reduction or joint methods, using family or unrelated individuals, and reducing the dimensionality inherent in these data. Most of the research teams regarded the use of multiple phenotypes as a means of increasing analytical power and as a way to clarify the biology of complex disease. Three major observations were gleaned from these Group 10 contributions. First, family and unrelated case-control samples are suited to finding different types of variants. In addition, collapsing either phenotypes or genotypes can reduce the dimensionality of the data and alleviate some of the problems of multiple testing. Finally, we were able to demonstrate in certain cases that performing a joint analysis of disease status and a quantitative trait can improve statistical power.

American journal of human biology : the official journal of the Human Biology Council, 2013

Objective: This research examines the coevolution of languages and uniparental genetic marker (mi... more Objective: This research examines the coevolution of languages and uniparental genetic marker (mitochondrial DNA [mtDNA] and nonrecombining Y-chromosome [NRY]) variation within five Lower Central American (Rama, Chorotega, Mal eku, Zapat on-Huetar, and Abrojo-Guaym ı) Amerindian groups. This pattern occurred since European contact.

Genetic epidemiology, 2014

The analysis of whole-genome sequence (WGS) data using longitudinal phenotypes offers a potential... more The analysis of whole-genome sequence (WGS) data using longitudinal phenotypes offers a potentially rich resource for the examination of the genetic variants and their covariates that affect complex phenotypes over time. We summarize eight contributions to the Genetic Analysis Workshop 18, which applied a diverse array of statistical genetic methods to analyze WGS data in combination with data from genome-wide association studies (GWAS) from up to four different time points on blood pressure phenotypes. The common goal of these analyses was to develop and apply appropriate methods that utilize longitudinal repeated measures to potentially increase the analytic efficiency of WGS and GWAS data. These diverse methods can be grouped into two categories, based on the way they model dependence structures: (1) linear mixed-effects (LME) models, where the random effect terms in the linear models are used to capture the dependence structures; and (2) variance-components models, where the dependence structures are constructed directly based on multiple components of variance-covariance matrices for the multivariate Gaussian responses. Despite the heterogeneous nature of these analytical methods, the group came to the following conclusions: (1) the use of repeat measurements can gain power to identify variants associated with the phenotype; (2) the inclusion of family data may correct genotyping errors and allow for more accurate detection of rare variants than using unrelated individuals only; and (3) fitting mixed-effects and variance-components models for longitudinal data presents computational challenges. The challenges and computational burden demanded by WGS data were addressed in the eight contributions.

American Journal of Human Biology, Jan 2011

"Objective: To identify genetic variation influencing serum bilirubin levels in American Indians,... more "Objective: To identify genetic variation influencing serum bilirubin levels in American Indians, we performed genome-wide screening and association analyses in the Strong Heart Family Study. Bilirubin is an endogenous antioxidant that has demonstrated an inverse relationship with cardiovascular disease. Genetic variation within the promoter region of uridine diphosphate glucuronosyltransferase (UGT1A1) on chromosome 2q has been associated with elevated serum bilirubin levels in European populations. However, no study has investigated the UGT1A1 promoter in American Indians.

Methods: Statistical analyses were carried out with 3,484 participants aged 14 to 93 years recruited from three geographic areas in the United States; Arizona, Oklahoma, and North and South Dakota.

Results: Variance components linkage analysis detected a quantitative trait locus (QTL) for bilirubin on chromosome 2q in the combined centers (LOD = 6.61, P = 4.24 × 10−6) and in Oklahoma (LOD = 5.65, P = 4.57 24 × 10−5). Genetic association of the UGT1A1 promoter polymorphism was significant for all geographic locations. After adjustment using conditional linkage for UGT1A1 promoter variance, the linkage signal dropped to 1.10 in the combined sample and to 3.32 (P = 0.02) in Oklahoma, indicating this polymorphism is not completely responsible for the linkage signal in American Indians. We also detected suggestive linkage signals in the Dakotas on chromosome 10p12 (LOD = 2.18) and in the combined centers (LOD = 2.24) on chromosome 10q21.

Conclusions: Replication of a serum bilirubin QTL on chromosome 2q in American Indians implicates UGT1A1 but further genotyping is warranted to identify additional causative polymorphisms. Evidence also supports a potential novel locus for bilirubin on chromosome 10.
"

Background Preeclampsia (PE) is a serious hypertensive pregnancy disorder with a significant gen... more Background

Preeclampsia (PE) is a serious hypertensive pregnancy disorder with a significant genetic component. Numerous genetic studies, including our own, have yielded many susceptibility genes from distinct functional groups. Additionally, transcriptome profiling of tissues at the maternal-fetal interface has likewise yielded many differentially expressed genes. Often there is little overlap between these two approaches, although genes identified in both approaches are significantly associated with PE. We have thus taken a novel integrative bioinformatics approach of analysing pathways common to the susceptibility genes and the PE transcriptome.

Methods

Using Illumina Human Ht12v4 and Wg6v3 BeadChips, transcriptome profiling was conducted on n = 65 normotensive and n = 60 PE decidua basalis tissues collected at delivery. The R software package libraries lumi and limma were used to preprocess transcript data for pathway analysis. Pathways were analysed and constructed using Pathway Studio. We examined ten candidate genes, which are from these functional groups: activin/inhibin signalling—ACVR1, ACVR1C, ACVR2A, INHA, INHBB; structural components—COL4A1, COL4A2 and M1 family aminopeptidases—ERAP1, ERAP2 and LNPEP.

Results/Conclusion

Major common regulators/targets of these susceptibility genes identified were AGT, IFNG, IL6, INHBA, SERPINE1, TGFB1 and VEGFA. The top two categories of pathways associated with the susceptibility genes, which were significantly altered in the PE decidual transcriptome, were apoptosis and cell signaling (p < 0.001). Thus, susceptibility genes from distinct functional groups share similar downstream pathways through common regulators/targets, some of which are altered in PE. This study contributes to a better understanding of how susceptibility genes may interact in the development of PE. With this knowledge, more targeted functional analyses of PE susceptibility genes in these key pathways can be performed to examine their contributions to the pathogenesis and severity of PE.

There has been increased interest in the underlying genetic mechanisms influencing serum bilirubi... more There has been increased interest in the underlying genetic mechanisms influencing serum bilirubin due to its antioxidant properties that have been shown to be protective against the development of cardiovascular disease and certain types of neoplasms, including Hodgkin's lymphoma and endometrial cancer. Recent research has shown genetic variation between ethnic populations and these differences have important implications for pharmacogenetic development, due to the role of serum bilirubin in the removal of biochemical toxins through glucuronidation.

… genetics: theory, methods …, Jan 1, 2007

Abstract: Current archaeological, biological and linguistic evidence points to a lower Central Am... more Abstract: Current archaeological, biological and linguistic evidence points to a lower Central American origin for Chibchan speaking populations who are thought to have continuously occupied the region for the last 105000 years. However, the biological relationship of these groups to Chibchan speakers from Northern South America remains largely unresolved.

This dissertation examined Y-Chromosome and mitochondrial DNA (mtDNA) genetic variation in 230 in... more This dissertation examined Y-Chromosome and mitochondrial DNA (mtDNA) genetic variation in 230 individuals from five (Rama, Chorotega, Huetar, Maléku, and Guaymi) indigenous populations inhabiting lower Central America in order to determine the evolutionary history and biological relationship among Chibchan-speakers and neighboring groups. Mitochondrial genetic diversity observed in Chibchan populations indicates a biological relationship with two Mesoamerican groups (Chorotega and K’iche Maya). However, Chibchan populations are biologically differentiated from eastern and Andean South American indigenous groups. Y-chromosome variation demonstrates a shared paternal biological relationship between Mesoamerican and northern Chibchan populations, whereas southern Chibchan and South American groups demonstrate a closer genetic association. Genetic diversity values in all five study populations were higher for Y-chromosome and lower for mtDNA haplotypes. Low mtDNA diversity and positive neutrality tests statistic values indicate that genetic drift has operated on this locus in Chibchan populations. Coalescent dates based on two haplogroup A2 (16360 and 16187) nodes indicate the divergence of Chibchan groups from earlier Paleoindian groups between 8,000 and 10,000 years ago. In addition, a genetic discontinuity was detected in Chibchan populations and is associated with the region around Lake Nicaragua. This discontinuity is connected with rising sea levels that occurred 8,000 years before present, separated lower Central from North and South America, and isolated the predecessors of modern Chibchan populations. Archaeological and linguistic evidence is used to support the endogenous development of Chibchan populations in lower Central America. Difference between low maternal and high paternal genetic diversities are interpreted as the result of two male dominated migrations. The first migration occurred with the arrival of Nahua and Oto-Manguean populations on the Pacific coast of Costa Rica and Nicaragua between 800 and 1000 A.D. The second migration occurred with European contact in the early sixteenth century. This study is concluded by supporting mtDNA evidence for the endogenous development of Chibchan-speaking populations in lower Central America. However, recent demographic events impacted the paternal genetic structure of these groups.