Yi-Ju Li - Academia.edu (original) (raw)

Papers by Yi-Ju Li

Research paper thumbnail of Genetic screen of African Americans with Fuchs endothelial corneal dystrophy

Molecular vision, 2013

Fuchs endothelial corneal dystrophy (FECD) is a genetically heterogeneous disorder that has been ... more Fuchs endothelial corneal dystrophy (FECD) is a genetically heterogeneous disorder that has been primarily studied in patients of European or Asian ancestry. Given the sparse literature on African Americans with FECD, we sought to characterize the genetic variation in three known FECD candidate genes in African American patients with FECD. Over an 8-year period, we enrolled 47 African American probands with FECD. All participants were clinically examined with slit-lamp biomicroscopy, and when corneal tissue specimens were available, histopathologic confirmation of the clinical diagnosis was obtained. The coding regions of known FECD susceptibility genes collagen, type VIII, alpha 2 (COL8A2); solute carrier family 4, sodium borate transporter, member 11 (SLC4A11); and zinc finger E-box binding homeobox 1 (ZEB1 [also known as TCF8]) were Sanger sequenced in the 47 probands using DNA isolated from blood samples. Twenty-two coding variants were detected across the COL8A2, SLC4A11, and Z...

Research paper thumbnail of Common MFRP sequence variants are not associated with moderate to high hyperopia, isolated microphthalmia, and high myopia

Molecular vision, Jan 4, 2008

The membrane-type frizzled-related protein (MFRP) gene is selectively expressed in the retinal pi... more The membrane-type frizzled-related protein (MFRP) gene is selectively expressed in the retinal pigment epithelium and ciliary body, and mutations of this gene cause nanophthalmos. The MFRP gene may not be essential for retinal function but has been hypothesized to play a role in ocular axial length regulation. The involvement of the MFRP gene in moderate to high hyperopic, isolated microphthalmic/anophthalmic, and high myopic patients was tested in two phases: a mutation screening/sequence variant discovery phase and a genetic association study phase. Eleven hyperopic, ten microphthalmic/anophthalmic, and seven non-syndromic high-grade myopic patients of varying ages and 11 control subjects participated in the mutation screening phase. Sixteen primer pairs were designed to amplify the 13 exons of the MFRP gene including intron/exon boundaries. Polymerase chain reactions were performed, and amplified products were sequenced using standard techniques. Normal and affected individual DN...

Research paper thumbnail of An International Collaborative Family-Based Whole-Genome Linkage Scan for High-Grade Myopia

Investigative Opthalmology & Visual Science, 2009

PURPOSE. Several nonsyndromic high-grade myopia loci have been mapped primarily by microsatellite... more PURPOSE. Several nonsyndromic high-grade myopia loci have been mapped primarily by microsatellite markers and a limited number of pedigrees. In this study, whole-genome linkage scans were performed for high-grade myopia, using single nucleotide polymorphisms (SNPs) in 254 families from five independent sites. METHODS. Genomic DNA samples from 1411 subjects were genotyped (Linkage Panel IVb; Illumina, San Diego, CA). Linkage analyses were performed on 1201 samples from 10 Asian, 12 African-American, and 221 Caucasian families, screening for 5744 SNPs after quality-control exclusions. Two disease states defined by sphere (SPH) and spherical equivalence (SE; sphereϩcylinder/2) were analyzed. Parametric and nonparametric two-point and multipoint linkage analyses were performed using the FASTLINK, HOMOG, and MERLIN programs. Multiple stratified datasets were examined, including overall, center-specific, and race-specific. Linkage regions were declared suggestive if they had a peak LOD score Ն 1.5. RESULTS. The MYP1, MYP3, MYP6, MYP11, MYP12, and MYP14 loci were replicated. The novel region q34.11 on chromosome 9 (max NPLϭ 2.07 at rs913275) was identified. Chromosome 12, region q21.2-24.12 (36.59 cM, MYP3 locus) showed significant linkage (peak HLOD ϭ 3.48) at rs337663 in the overall dataset by SPH and was detected by the Duke, Asian, and Caucasian subsets as well. Potential shared interval was race dependent-a 9.4-cM region (rs163016-rs1520724) driven by From the 1 Center for Human Genetics and the Departments of and

Research paper thumbnail of Evaluation of the X-Linked High-Grade Myopia Locus (MYP1) with Cone Dysfunction and Color Vision Deficiencies

Investigative Opthalmology & Visual Science, 2009

Purpose-X-linked high myopia with mild cone dysfunction and color vision defects has been mapped ... more Purpose-X-linked high myopia with mild cone dysfunction and color vision defects has been mapped to chromosome Xq28 (MYP1 locus). CXorf2/TEX28 is a nested, intercalated gene within the red-green opsin cone pigment gene tandem array on Xq28. The authors investigated whether TEX28 gene alterations were associated with the Xq28-linked myopia phenotype. Genomic DNA from five pedigrees (with high myopia and either protanopia or deuteranopia) that mapped to Xq28 were screened for TEX28 copy number variations (CNVs) and sequence variants. Methods-To examine for CNVs, ultra-high resolution array-comparative genomic hybridization (array-CGH) assays were performed comparing the subject genomic DNA with control samples (two pairs from two pedigrees). Opsin or TEX28 gene-targeted quantitative real-time gene expression assays (comparative CT method) were performed to validate the array-CGH findings. All exons of TEX28, including intron/exon boundaries, were amplified and sequenced using standard techniques. Results-Array-CGH findings revealed predicted duplications in affected patient samples. Although only three copies of TEX28 were previously reported within the opsin array, quantitative real-time analysis of the TEX28 targeted assay of affected male or carrier female individuals in these pedigrees revealed either fewer (one) or more (four or five) copies than did related and control unaffected individuals. Sequence analysis of TEX28 did not reveal any variants associated with the disease status. Conclusions-CNVs have been proposed to play a role in disease inheritance and susceptibility as they affect gene dosage. TEX28 gene CNVs appear to be associated with the MYP1 X-linked myopia phenotypes.

Research paper thumbnail of Application of a rank-based genetic association test to age-at-onset data from the Collaborative Study on the Genetics of Alcoholism study

BMC Genetics, 2005

Association studies of quantitative traits have often relied on methods in which a normal distrib... more Association studies of quantitative traits have often relied on methods in which a normal distribution of the trait is assumed. However, quantitative phenotypes from complex human diseases are often censored, highly skewed, or contaminated with outlying values. We recently developed a rank-based association method that takes into account censoring and makes no distributional assumptions about the trait. In this study, we applied our new method to age-at-onset data on ALDX1 and ALDX2. Both traits are highly skewed (skewness > 1.9) and often censored. We performed a whole genome association study of age at onset of the ALDX1 trait using Illumina single-nucleotide polymorphisms. Only slightly more than 5% of markers were significant. However, we identified two regions on chromosomes 14 and 15, which each have at least four significant markers clustering together. These two regions may harbor genes that regulate age at onset of ALDX1 and ALDX2. Future fine mapping of these two region...

Research paper thumbnail of Family-based association tests for rare variants with censored traits

Research paper thumbnail of Genome-Wide Association Studies Reveal Genetic Variants in CTNND2 for High Myopia in Singapore Chinese

Ophthalmology, 2011

Objective-To determine susceptibility genes for high myopia in Singaporean Chinese. Design-A meta... more Objective-To determine susceptibility genes for high myopia in Singaporean Chinese. Design-A meta-analysis of two genome wide association (GWA) datasets in Chinese and a follow-up replication cohort in Japanese. Participants and Controls-Two independent datasets of Singaporean Chinese individuals aged 10-12 years (SCORM-Singapore Cohort Study of the Risk factors for Myopia: cases=65, controls=238) and aged > 21 years (SP2-Singapore Prospective Study Program: cases=222, controls=435) for GWA studies, and a Japanese dataset aged >20 years (cases=959, controls=2128) for replication. Methods-Genomic DNA samples from SCORM and SP2 were genotyped using various Illumina Beadarray platforms (> HumanHap 500). Single-locus association tests were conducted for each dataset with meta-analysis using pooled z-scores. The top-ranked genetic markers were examined for replication in Japanese dataset. Fisher's P was calculated for the combined analysis of all three cohorts. Main outcome measures-High myopia, defined by spherical equivalent (SE) ≤ −6.00 diopters (D); controls defined by SE between −0.50D and +1.00D. Results-Two SNPs (rs12716080 and rs6885224) in the gene CTNND2 on chromosome 5p15 ranked top in the meta-analysis of our Chinese datasets (meta-P = 1.14×10 −5 and meta-P = 1.51×10 −5 , respectively) with strong supporting evidence in each individual dataset analysis (Max P = 1.85.x10 −4 in SCORM: Max P = 8.8×10 −3 in SP2). Evidence of replication was observed in Japanese dataset for rs6885224 (P = 0.035, meta-P of three datasets: 7.84×10 −6). Conclusion-This study identified strong association of CTNND2 for high myopia in Asian datasets. The CTNND2 gene maps to a known high myopia linkage region on chromosome 5p15.

Research paper thumbnail of Genome-wide association study identifies three novel loci in Fuchs endothelial corneal dystrophy

Nature communications, Mar 30, 2017

The structure of the cornea is vital to its transparency, and dystrophies that disrupt corneal or... more The structure of the cornea is vital to its transparency, and dystrophies that disrupt corneal organization are highly heritable. To understand the genetic aetiology of Fuchs endothelial corneal dystrophy (FECD), the most prevalent corneal disorder requiring transplantation, we conducted a genome-wide association study (GWAS) on 1,404 FECD cases and 2,564 controls of European ancestry, followed by replication and meta-analysis, for a total of 2,075 cases and 3,342 controls. We identify three novel loci meeting genome-wide significance (P<5 × 10(-8)): KANK4 rs79742895, LAMC1 rs3768617 and LINC00970/ATP1B1 rs1200114. We also observe an overwhelming effect of the established TCF4 locus. Interestingly, we detect differential sex-specific association at LAMC1, with greater risk in women, and TCF4, with greater risk in men. Combining GWAS results with biological evidence we expand the knowledge of common FECD loci from one to four, and provide a deeper understanding of the underlying p...

Research paper thumbnail of Age at onset in two common neurodegenerative diseases is genetically controlled

American Journal of Human Genetics, 2002

To identify genes influencing age at onset (AAO) in two common neurodegenerative diseases, a geno... more To identify genes influencing age at onset (AAO) in two common neurodegenerative diseases, a genomic screen was performed for AAO in families with Alzheimer disease (AD; n= 449) and Parkinson disease (PD; n= 174). Heritabilities between 40%–60% were ...

Research paper thumbnail of Glutathione S-transferase omega-1 modifies age-at-onset of Alzheimer disease …

Human molecular …, 2003

We previously reported genetic linkage of loci controlling age-at-onset in Alzheimer disease (AD)... more We previously reported genetic linkage of loci controlling age-at-onset in Alzheimer disease (AD) and Parkinson's disease (PD) to a 15 cM region on chromosome 10q. Given the large number of genes in this initial starting region, we applied the process of 'genomic convergence' to ...

Research paper thumbnail of Characterization of cultured thymus tissue used for transplantation with emphasis on promiscuous expression of thyroid tissue-specific genes

Immunologic Research, 2009

Autoimmune thyroid disease occurs in some complete DiGeorge anomaly patients after thymus transpl... more Autoimmune thyroid disease occurs in some complete DiGeorge anomaly patients after thymus transplantation. This study was designed to assess the effect of culture of thymus tissue on the expression of genes involved in the development of autoimmunity. The expression of autoimmune regulator (AIRE), thyroglobulin (TG), thyroid peroxidase (TPO), and cytokeratin RNAs was examined in thymocytes and thymus tissue on the day of thymus harvest and after 14 and 21 days of culture. Immunohistochemistry was used to evaluate the cytokeratin expression in the thymus tissue. AIRE, TG, TPO, and cytokeratin mRNAs were found in harvest-day, 14-day and 21-day cultured tissues. Levels of AIRE, TG, and cytokeratin mRNAs were mostly higher after culture compared to expression on the harvest day, likely secondary to thymocyte depletion.

Research paper thumbnail of Molecular clock and recombination in primate Mhc genes

Immunological Reviews, 1999

Summary: To set an accurate chronological framework to the evolution of primate class I and II ge... more Summary: To set an accurate chronological framework to the evolution of primate class I and II genes in the major histocompatibility complex (Mhc), the rate of silent nucleotide substitutions in exons and introns is examined for various cDNA and genom sequences currently available. The rate is sensitive to the GC content and correlates negatively with increased GC biases at the third codon positions of Mhc genes. The intergenic recombination rate in the HLA region is estimated from the synonymous nucleotide differences at 37 linked loci. Any HLA subregion is recombined more or less at the ordinary rate of 1 cM per 1 Mb, although the rate may be reduced in some subregions. This information is used to discuss HLA haplotypes when they are applied to studies of human demography The unusual polymorphism in the α-helix of HLA-DRB1 is also revisited in relation to intragenic recombination, but the molecular mechanism and the evolutionary cause both remain enigmatic.

Research paper thumbnail of THE NEUTRAL THEORY AND NATURAL SELECTION IN THE HLA REGION

TABLE OF CONTENTS 1. Abstract 2. Introduction 3. Genes and nucleotide differences in HLA 4. Inter... more TABLE OF CONTENTS 1. Abstract 2. Introduction 3. Genes and nucleotide differences in HLA 4. Intergenic recombination 5. DRB1 allelic lineages and disease association 6. Perspective 7. Acknowledgments 8. References

Research paper thumbnail of Paleo-demography of the Drosophila melanogaster subgroup. Application of the maximum likelihood method

Genes & Genetic Systems, 1999

The species divergence times and demographic histories of Drosophila melanogaster and its three s... more The species divergence times and demographic histories of Drosophila melanogaster and its three sibling species, D. mauritiana, D. simulans, and D. yakuba, were investigated using a maximum likelihood (ML) method. Thirty-nine orthologous loci for these four species were retrieved from DDBJ/EMBL/GenBank database. Both autosomal and X-linked loci were used in this study. A significant degree of rate heterogeneity across loci was observed for each pair of species. Most loci have the GC content greater than 50% at the third codon position. The codon usage bias in Drosophila loci is considered to result in the high GC content and the heterogenous rates across loci. The chi-square, G, and Fisher&#39;s exact tests indicated that data sets with 11, 23, and 9 pairs of DNA sequences for the comparison of D. melanogaster with D. mauritiana, D. simulans, and D. yakuba, respectively, retain homogeneous rates across loci. We applied the ML method to these data sets to estimate the DNA sequence divergences before and after speciation of each species pair along with their standard deviations. Using 1.6 x 10(-8) as the rate of nucleotide substitutions per silent site per year, our results indicate that the D. melanogaster lineage split from D. yakuba approximately 5.1 +/- 0.8 million years ago (mya), D. mauritiana 2.7 +/- 0.4 mya, and D. simulans 2.3 +/- 0.3 mya. It implies that D. melanogaster became distinct from D. mauritiana and D. simulans at approximately the same time and from D. yakuba no earlier than 10 mya. The effective ancestral population size of D. melanogaster appears to be stable over evolutionary time. Assuming 10 generations per year for Drosophila, the effective population size in the ancestral lineage immediately prior to the time of species divergence is approximately 3 x 10(6), which is close to that estimated for the extant D. melanogaster population. The D. melanogaster did not encounter any obvious bottleneck during the past 10 million years.

Research paper thumbnail of NOS2A and the modulating effect of cigarette smoking in Parkinson's disease

Annals of Neurology, 2006

ObjectiveInducible nitric oxide synthase, a protein product of NOS2A, generates nitric oxide as a... more ObjectiveInducible nitric oxide synthase, a protein product of NOS2A, generates nitric oxide as a defense mechanism, but excessive levels threaten cellular survival. NOS2A is a candidate gene for Parkinson's disease (PD) that potentially interacts with cigarette smoking. We examined NOS2A for association with PD risk and age at onset (AAO) and for interaction with smoking.Inducible nitric oxide synthase, a protein product of NOS2A, generates nitric oxide as a defense mechanism, but excessive levels threaten cellular survival. NOS2A is a candidate gene for Parkinson's disease (PD) that potentially interacts with cigarette smoking. We examined NOS2A for association with PD risk and age at onset (AAO) and for interaction with smoking.MethodsWe genotyped 13 NOS2A single nucleotide polymorphisms (SNPs) in 466 singleton families and in a validation set of 286 multiplex families. We tested allelic and haplotypic association using the association in the presence of linkage test, genotypic associations using the genotype pedigree disequilibrium test, AAO effects using the quantitative transmission disequilibrium test, and interactions using generalized estimating equations.We genotyped 13 NOS2A single nucleotide polymorphisms (SNPs) in 466 singleton families and in a validation set of 286 multiplex families. We tested allelic and haplotypic association using the association in the presence of linkage test, genotypic associations using the genotype pedigree disequilibrium test, AAO effects using the quantitative transmission disequilibrium test, and interactions using generalized estimating equations.ResultsAmong the pooled earliest onset families, rs2255929 and rs1060826 generated significant allelic (p = 0.000059 and 0.0062, respectively) and genotypic (p = 0.0039 and 0.0014, respectively) associations with risk and AAO (p = 0.00070 and 0.0073, respectively); the two-SNP haplotype generated even stronger association with PD (p = 0.000013). Significant interactions with smoking (p = 0.0015 for rs 2255929 and p < 0.0001 for rs 1060826) were detected in a subset of the families; smoking was inversely associated with PD among risk allele noncarriers, but significance diminished among carriers.Among the pooled earliest onset families, rs2255929 and rs1060826 generated significant allelic (p = 0.000059 and 0.0062, respectively) and genotypic (p = 0.0039 and 0.0014, respectively) associations with risk and AAO (p = 0.00070 and 0.0073, respectively); the two-SNP haplotype generated even stronger association with PD (p = 0.000013). Significant interactions with smoking (p = 0.0015 for rs 2255929 and p < 0.0001 for rs 1060826) were detected in a subset of the families; smoking was inversely associated with PD among risk allele noncarriers, but significance diminished among carriers.InterpretationOur findings support NOS2A as a genetic risk factor in PD, potentially by influencing AAO and by modifying the inverse association between PD and smoking. Ann Neurol 2006Our findings support NOS2A as a genetic risk factor in PD, potentially by influencing AAO and by modifying the inverse association between PD and smoking. Ann Neurol 2006

Research paper thumbnail of Genomic convergence to identify candidate genes for Parkinson disease: SAGE analysis of the substantia nigra

Movement Disorders, 2005

Genomic convergence is a multistep approach that combines gene expression with genomic linkage to... more Genomic convergence is a multistep approach that combines gene expression with genomic linkage to identify and prioritize susceptibility genes for complex disease. As a first step, we previously performed linkage analysis on 174 multiplex Parkinson's disease (PD) families, identifying five peaks for PD risk and two for genes affecting age at onset (AAO) in PD [Hauser et al., Hum Mol Genet 2003;12:671–677]. We report here the next step: serial analysis of gene expression [SAGE; Scott et al., JAMA 2001;286:2239–2242] to analyze substantia nigra tissue from three PD patients and two age-matched controls. We find 933 differentially expressed genes (P < 0.05) between PD and controls, but of these, only 50 genes represented by unique SAGE tags map within our previously described PD linkage regions. Furthermore, genes encoded by mitochondrial DNA are expressed 1.5-fold higher in PD patients versus controls, without an increase in the corresponding nuclear-encoded mitochondrial components, suggesting an increase in mtDNA genomes in PD or a disjunction with nuclear expression. The next step in the genomic convergence process will be to screen these 50 high-quality candidate genes for association with PD risk susceptibility and genetic effects on AAO. © 2005 Movement Disorder Society

Research paper thumbnail of Methods for interaction analyses using family-based case-control data: conditional logistic regression versus generalized estimating equations

Genetic Epidemiology, 2007

A complex web of gene-gene and gene-environment interactions likely underlies late-onset disease ... more A complex web of gene-gene and gene-environment interactions likely underlies late-onset disease development. We compared conditional logistic regression (CLR) and generalized estimating equations (GEE) in modeling such interactions in pedigrees with missing parents. Using the simulation of linkage and association (SIMLA) program, disease genes, an environmental risk factor, gene-gene interaction, and gene-environment interaction were generated in family-based data sets. Four scenarios for the relationship between the marker and disease loci were examined: linkage and association, linkage without association, association without linkage, and absence of both linkage and association. Models for CLR and GEE (with exchangeable and independence correlation matrices) were built, and type I error, power, average odds ratio (OR), standard deviation, and 95% confidence intervals were estimated. CLR and GEE were valid tests of association in the presence of linkage, but type I error was inflated for association without linkage, particularly with GEE. CLR generated estimates of the OR with lower bias but often more variability than the OR estimates observed for GEE. Further, GEE was more powerful than CLR in detecting main and interactive effects. Although GEE with both matrices had similar power, use of the independence matrix resulted in lower type I error and less biased OR estimation as compared to the exchangeable matrix. Our findings support the use of GEE in maximizing power to detect gene-gene and gene-environment interactions but caution its use under potential association without linkage (e.g., population stratification) and the interpretation of its OR estimates. Genet. Epidemiol. 2007. © 2007 Wiley-Liss, Inc.

Research paper thumbnail of Expression Profiling of Substantia Nigra in Parkinson Disease, Progressive Supranuclear Palsy, and Frontotemporal Dementia With Parkinsonism

Archives of Neurology, 2005

Parkinson disease (PD) is characterized by loss of dopaminergic neurons in the substantia nigra. ... more Parkinson disease (PD) is characterized by loss of dopaminergic neurons in the substantia nigra. Genes contributing to rare mendelian forms of PD have been identified, but the genes involved in the more common idiopathic PD are not well understood. To identify genes important to PD pathogenesis using microarrays and to investigate their potential to aid in diagnosing parkinsonism. Microarray expression analysis of postmortem substantia nigra tissue. Substantia nigra samples from 14 unrelated individuals were analyzed, including 6 with PD, 2 with progressive supranuclear palsy, 1 with frontotemporal dementia with parkinsonism, and 5 control subjects. Identification of genes significantly differentially expressed (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;.05) using Affymetrix U133A microarrays. There were 142 genes that were significantly differentially expressed between PD cases and controls and 96 genes that were significantly differentially expressed between the combined progressive supranuclear palsy and frontotemporal dementia with parkinsonism cases and controls. The 12 genes common to all 3 disorders may be related to secondary effects. Hierarchical cluster analysis after exclusion of these 12 genes differentiated 4 of the 6 PD cases from progressive supranuclear palsy and frontotemporal dementia with parkinsonism. Four main molecular pathways are altered in PD substantia nigra: chaperones, ubiquitination, vesicle trafficking, and nuclear-encoded mitochondrial genes. These results correlate well with expression analyses performed in several PD animal models. Expression analyses have promising potential to aid in postmortem diagnostic evaluation of parkinsonism.

Research paper thumbnail of Identification of Risk and Age-at-Onset Genes on Chromosome 1p in Parkinson Disease

American Journal of Human Genetics, 2005

We previously reported a linkage region on chromosome 1p (LOD p 3.41) for genes controlling age a... more We previously reported a linkage region on chromosome 1p (LOD p 3.41) for genes controlling age at onset (AAO) in Parkinson disease (PD). This region overlaps with the previously reported PARK10 locus. To identify the gene(s) associated with AAO and risk of PD in this region, we first applied a genomic convergence approach that combined gene expression and linkage data. No significant results were found. Second, we performed association mapping across a 19.2-Mb region centered under the AAO linkage peak. An iterative association mapping approach was done by initially genotyping single-nucleotide polymorphisms at an average distance of 100 kb apart and then by increasing the density of markers as needed. Using the overall data set of 267 multiplex families, we identified six associated genes in the region, but further screening of a subset of 83 families linked to the chromosome 1 locus identified only two genes significantly associated with AAO in PD: the g subunit of the translation initiation factor EIF2B gene (EIF2B3), which was more significant in the linked subset and the ubiquitin-specific protease 24 gene (USP24). Unexpectedly, the human immunodeficiency virus enhancer-binding protein 3 gene (HIVEP3) was found to be associated with risk for susceptibility to PD. We used several criteria to define significant results in the presence of multiple testing, including criteria derived from a novel cluster approach. The known or putative functions of these genes fit well with the current suspected pathogenic mechanisms of PD and thus show great potential as candidates for the PARK10 locus.

Research paper thumbnail of Genome-wide Association Study Implicates a Chromosome 12 Risk Locus for Late-Onset Alzheimer Disease

American Journal of Human Genetics, 2009

Many candidate genes have been studied for asthma, but replication has varied. Novel candidate ge... more Many candidate genes have been studied for asthma, but replication has varied. Novel candidate genes have been identified for various complex diseases using genome-wide association studies (GWASs). We conducted a GWAS in 492 Mexican children with asthma, predominantly atopic by skin prick test, and their parents using the Illumina HumanHap 550 K BeadChip to identify novel genetic variation for childhood asthma. The 520,767 autosomal single nucleotide polymorphisms (SNPs) passing quality control were tested for association with childhood asthma using log-linear regression with a log-additive risk model. Eleven of the most significantly associated GWAS SNPs were tested for replication in an independent study of 177 Mexican case-parent trios with childhood-onset asthma and atopy using log-linear analysis. The chromosome 9q21.31 SNP rs2378383 (p = 7.10610 26 in the GWAS), located upstream of transducin-like enhancer of split 4 (TLE4), gave a p-value of 0.03 and the same direction and magnitude of association in the replication study (combined p = 6.79610 27 ). Ancestry analysis on chromosome 9q supported an inverse association between the rs2378383 minor allele (G) and childhood asthma. This work identifies chromosome 9q21.31 as a novel susceptibility locus for childhood asthma in Mexicans. Further, analysis of genome-wide expression data in 51 human tissues from the Novartis Research Foundation showed that median GWAS significance levels for SNPs in genes expressed in the lung differed most significantly from genes not expressed in the lung when compared to 50 other tissues, supporting the biological plausibility of our overall GWAS findings and the multigenic etiology of childhood asthma.

Research paper thumbnail of Genetic screen of African Americans with Fuchs endothelial corneal dystrophy

Molecular vision, 2013

Fuchs endothelial corneal dystrophy (FECD) is a genetically heterogeneous disorder that has been ... more Fuchs endothelial corneal dystrophy (FECD) is a genetically heterogeneous disorder that has been primarily studied in patients of European or Asian ancestry. Given the sparse literature on African Americans with FECD, we sought to characterize the genetic variation in three known FECD candidate genes in African American patients with FECD. Over an 8-year period, we enrolled 47 African American probands with FECD. All participants were clinically examined with slit-lamp biomicroscopy, and when corneal tissue specimens were available, histopathologic confirmation of the clinical diagnosis was obtained. The coding regions of known FECD susceptibility genes collagen, type VIII, alpha 2 (COL8A2); solute carrier family 4, sodium borate transporter, member 11 (SLC4A11); and zinc finger E-box binding homeobox 1 (ZEB1 [also known as TCF8]) were Sanger sequenced in the 47 probands using DNA isolated from blood samples. Twenty-two coding variants were detected across the COL8A2, SLC4A11, and Z...

Research paper thumbnail of Common MFRP sequence variants are not associated with moderate to high hyperopia, isolated microphthalmia, and high myopia

Molecular vision, Jan 4, 2008

The membrane-type frizzled-related protein (MFRP) gene is selectively expressed in the retinal pi... more The membrane-type frizzled-related protein (MFRP) gene is selectively expressed in the retinal pigment epithelium and ciliary body, and mutations of this gene cause nanophthalmos. The MFRP gene may not be essential for retinal function but has been hypothesized to play a role in ocular axial length regulation. The involvement of the MFRP gene in moderate to high hyperopic, isolated microphthalmic/anophthalmic, and high myopic patients was tested in two phases: a mutation screening/sequence variant discovery phase and a genetic association study phase. Eleven hyperopic, ten microphthalmic/anophthalmic, and seven non-syndromic high-grade myopic patients of varying ages and 11 control subjects participated in the mutation screening phase. Sixteen primer pairs were designed to amplify the 13 exons of the MFRP gene including intron/exon boundaries. Polymerase chain reactions were performed, and amplified products were sequenced using standard techniques. Normal and affected individual DN...

Research paper thumbnail of An International Collaborative Family-Based Whole-Genome Linkage Scan for High-Grade Myopia

Investigative Opthalmology & Visual Science, 2009

PURPOSE. Several nonsyndromic high-grade myopia loci have been mapped primarily by microsatellite... more PURPOSE. Several nonsyndromic high-grade myopia loci have been mapped primarily by microsatellite markers and a limited number of pedigrees. In this study, whole-genome linkage scans were performed for high-grade myopia, using single nucleotide polymorphisms (SNPs) in 254 families from five independent sites. METHODS. Genomic DNA samples from 1411 subjects were genotyped (Linkage Panel IVb; Illumina, San Diego, CA). Linkage analyses were performed on 1201 samples from 10 Asian, 12 African-American, and 221 Caucasian families, screening for 5744 SNPs after quality-control exclusions. Two disease states defined by sphere (SPH) and spherical equivalence (SE; sphereϩcylinder/2) were analyzed. Parametric and nonparametric two-point and multipoint linkage analyses were performed using the FASTLINK, HOMOG, and MERLIN programs. Multiple stratified datasets were examined, including overall, center-specific, and race-specific. Linkage regions were declared suggestive if they had a peak LOD score Ն 1.5. RESULTS. The MYP1, MYP3, MYP6, MYP11, MYP12, and MYP14 loci were replicated. The novel region q34.11 on chromosome 9 (max NPLϭ 2.07 at rs913275) was identified. Chromosome 12, region q21.2-24.12 (36.59 cM, MYP3 locus) showed significant linkage (peak HLOD ϭ 3.48) at rs337663 in the overall dataset by SPH and was detected by the Duke, Asian, and Caucasian subsets as well. Potential shared interval was race dependent-a 9.4-cM region (rs163016-rs1520724) driven by From the 1 Center for Human Genetics and the Departments of and

Research paper thumbnail of Evaluation of the X-Linked High-Grade Myopia Locus (MYP1) with Cone Dysfunction and Color Vision Deficiencies

Investigative Opthalmology & Visual Science, 2009

Purpose-X-linked high myopia with mild cone dysfunction and color vision defects has been mapped ... more Purpose-X-linked high myopia with mild cone dysfunction and color vision defects has been mapped to chromosome Xq28 (MYP1 locus). CXorf2/TEX28 is a nested, intercalated gene within the red-green opsin cone pigment gene tandem array on Xq28. The authors investigated whether TEX28 gene alterations were associated with the Xq28-linked myopia phenotype. Genomic DNA from five pedigrees (with high myopia and either protanopia or deuteranopia) that mapped to Xq28 were screened for TEX28 copy number variations (CNVs) and sequence variants. Methods-To examine for CNVs, ultra-high resolution array-comparative genomic hybridization (array-CGH) assays were performed comparing the subject genomic DNA with control samples (two pairs from two pedigrees). Opsin or TEX28 gene-targeted quantitative real-time gene expression assays (comparative CT method) were performed to validate the array-CGH findings. All exons of TEX28, including intron/exon boundaries, were amplified and sequenced using standard techniques. Results-Array-CGH findings revealed predicted duplications in affected patient samples. Although only three copies of TEX28 were previously reported within the opsin array, quantitative real-time analysis of the TEX28 targeted assay of affected male or carrier female individuals in these pedigrees revealed either fewer (one) or more (four or five) copies than did related and control unaffected individuals. Sequence analysis of TEX28 did not reveal any variants associated with the disease status. Conclusions-CNVs have been proposed to play a role in disease inheritance and susceptibility as they affect gene dosage. TEX28 gene CNVs appear to be associated with the MYP1 X-linked myopia phenotypes.

Research paper thumbnail of Application of a rank-based genetic association test to age-at-onset data from the Collaborative Study on the Genetics of Alcoholism study

BMC Genetics, 2005

Association studies of quantitative traits have often relied on methods in which a normal distrib... more Association studies of quantitative traits have often relied on methods in which a normal distribution of the trait is assumed. However, quantitative phenotypes from complex human diseases are often censored, highly skewed, or contaminated with outlying values. We recently developed a rank-based association method that takes into account censoring and makes no distributional assumptions about the trait. In this study, we applied our new method to age-at-onset data on ALDX1 and ALDX2. Both traits are highly skewed (skewness > 1.9) and often censored. We performed a whole genome association study of age at onset of the ALDX1 trait using Illumina single-nucleotide polymorphisms. Only slightly more than 5% of markers were significant. However, we identified two regions on chromosomes 14 and 15, which each have at least four significant markers clustering together. These two regions may harbor genes that regulate age at onset of ALDX1 and ALDX2. Future fine mapping of these two region...

Research paper thumbnail of Family-based association tests for rare variants with censored traits

Research paper thumbnail of Genome-Wide Association Studies Reveal Genetic Variants in CTNND2 for High Myopia in Singapore Chinese

Ophthalmology, 2011

Objective-To determine susceptibility genes for high myopia in Singaporean Chinese. Design-A meta... more Objective-To determine susceptibility genes for high myopia in Singaporean Chinese. Design-A meta-analysis of two genome wide association (GWA) datasets in Chinese and a follow-up replication cohort in Japanese. Participants and Controls-Two independent datasets of Singaporean Chinese individuals aged 10-12 years (SCORM-Singapore Cohort Study of the Risk factors for Myopia: cases=65, controls=238) and aged > 21 years (SP2-Singapore Prospective Study Program: cases=222, controls=435) for GWA studies, and a Japanese dataset aged >20 years (cases=959, controls=2128) for replication. Methods-Genomic DNA samples from SCORM and SP2 were genotyped using various Illumina Beadarray platforms (> HumanHap 500). Single-locus association tests were conducted for each dataset with meta-analysis using pooled z-scores. The top-ranked genetic markers were examined for replication in Japanese dataset. Fisher's P was calculated for the combined analysis of all three cohorts. Main outcome measures-High myopia, defined by spherical equivalent (SE) ≤ −6.00 diopters (D); controls defined by SE between −0.50D and +1.00D. Results-Two SNPs (rs12716080 and rs6885224) in the gene CTNND2 on chromosome 5p15 ranked top in the meta-analysis of our Chinese datasets (meta-P = 1.14×10 −5 and meta-P = 1.51×10 −5 , respectively) with strong supporting evidence in each individual dataset analysis (Max P = 1.85.x10 −4 in SCORM: Max P = 8.8×10 −3 in SP2). Evidence of replication was observed in Japanese dataset for rs6885224 (P = 0.035, meta-P of three datasets: 7.84×10 −6). Conclusion-This study identified strong association of CTNND2 for high myopia in Asian datasets. The CTNND2 gene maps to a known high myopia linkage region on chromosome 5p15.

Research paper thumbnail of Genome-wide association study identifies three novel loci in Fuchs endothelial corneal dystrophy

Nature communications, Mar 30, 2017

The structure of the cornea is vital to its transparency, and dystrophies that disrupt corneal or... more The structure of the cornea is vital to its transparency, and dystrophies that disrupt corneal organization are highly heritable. To understand the genetic aetiology of Fuchs endothelial corneal dystrophy (FECD), the most prevalent corneal disorder requiring transplantation, we conducted a genome-wide association study (GWAS) on 1,404 FECD cases and 2,564 controls of European ancestry, followed by replication and meta-analysis, for a total of 2,075 cases and 3,342 controls. We identify three novel loci meeting genome-wide significance (P<5 × 10(-8)): KANK4 rs79742895, LAMC1 rs3768617 and LINC00970/ATP1B1 rs1200114. We also observe an overwhelming effect of the established TCF4 locus. Interestingly, we detect differential sex-specific association at LAMC1, with greater risk in women, and TCF4, with greater risk in men. Combining GWAS results with biological evidence we expand the knowledge of common FECD loci from one to four, and provide a deeper understanding of the underlying p...

Research paper thumbnail of Age at onset in two common neurodegenerative diseases is genetically controlled

American Journal of Human Genetics, 2002

To identify genes influencing age at onset (AAO) in two common neurodegenerative diseases, a geno... more To identify genes influencing age at onset (AAO) in two common neurodegenerative diseases, a genomic screen was performed for AAO in families with Alzheimer disease (AD; n= 449) and Parkinson disease (PD; n= 174). Heritabilities between 40%–60% were ...

Research paper thumbnail of Glutathione S-transferase omega-1 modifies age-at-onset of Alzheimer disease …

Human molecular …, 2003

We previously reported genetic linkage of loci controlling age-at-onset in Alzheimer disease (AD)... more We previously reported genetic linkage of loci controlling age-at-onset in Alzheimer disease (AD) and Parkinson's disease (PD) to a 15 cM region on chromosome 10q. Given the large number of genes in this initial starting region, we applied the process of 'genomic convergence' to ...

Research paper thumbnail of Characterization of cultured thymus tissue used for transplantation with emphasis on promiscuous expression of thyroid tissue-specific genes

Immunologic Research, 2009

Autoimmune thyroid disease occurs in some complete DiGeorge anomaly patients after thymus transpl... more Autoimmune thyroid disease occurs in some complete DiGeorge anomaly patients after thymus transplantation. This study was designed to assess the effect of culture of thymus tissue on the expression of genes involved in the development of autoimmunity. The expression of autoimmune regulator (AIRE), thyroglobulin (TG), thyroid peroxidase (TPO), and cytokeratin RNAs was examined in thymocytes and thymus tissue on the day of thymus harvest and after 14 and 21 days of culture. Immunohistochemistry was used to evaluate the cytokeratin expression in the thymus tissue. AIRE, TG, TPO, and cytokeratin mRNAs were found in harvest-day, 14-day and 21-day cultured tissues. Levels of AIRE, TG, and cytokeratin mRNAs were mostly higher after culture compared to expression on the harvest day, likely secondary to thymocyte depletion.

Research paper thumbnail of Molecular clock and recombination in primate Mhc genes

Immunological Reviews, 1999

Summary: To set an accurate chronological framework to the evolution of primate class I and II ge... more Summary: To set an accurate chronological framework to the evolution of primate class I and II genes in the major histocompatibility complex (Mhc), the rate of silent nucleotide substitutions in exons and introns is examined for various cDNA and genom sequences currently available. The rate is sensitive to the GC content and correlates negatively with increased GC biases at the third codon positions of Mhc genes. The intergenic recombination rate in the HLA region is estimated from the synonymous nucleotide differences at 37 linked loci. Any HLA subregion is recombined more or less at the ordinary rate of 1 cM per 1 Mb, although the rate may be reduced in some subregions. This information is used to discuss HLA haplotypes when they are applied to studies of human demography The unusual polymorphism in the α-helix of HLA-DRB1 is also revisited in relation to intragenic recombination, but the molecular mechanism and the evolutionary cause both remain enigmatic.

Research paper thumbnail of THE NEUTRAL THEORY AND NATURAL SELECTION IN THE HLA REGION

TABLE OF CONTENTS 1. Abstract 2. Introduction 3. Genes and nucleotide differences in HLA 4. Inter... more TABLE OF CONTENTS 1. Abstract 2. Introduction 3. Genes and nucleotide differences in HLA 4. Intergenic recombination 5. DRB1 allelic lineages and disease association 6. Perspective 7. Acknowledgments 8. References

Research paper thumbnail of Paleo-demography of the Drosophila melanogaster subgroup. Application of the maximum likelihood method

Genes & Genetic Systems, 1999

The species divergence times and demographic histories of Drosophila melanogaster and its three s... more The species divergence times and demographic histories of Drosophila melanogaster and its three sibling species, D. mauritiana, D. simulans, and D. yakuba, were investigated using a maximum likelihood (ML) method. Thirty-nine orthologous loci for these four species were retrieved from DDBJ/EMBL/GenBank database. Both autosomal and X-linked loci were used in this study. A significant degree of rate heterogeneity across loci was observed for each pair of species. Most loci have the GC content greater than 50% at the third codon position. The codon usage bias in Drosophila loci is considered to result in the high GC content and the heterogenous rates across loci. The chi-square, G, and Fisher&#39;s exact tests indicated that data sets with 11, 23, and 9 pairs of DNA sequences for the comparison of D. melanogaster with D. mauritiana, D. simulans, and D. yakuba, respectively, retain homogeneous rates across loci. We applied the ML method to these data sets to estimate the DNA sequence divergences before and after speciation of each species pair along with their standard deviations. Using 1.6 x 10(-8) as the rate of nucleotide substitutions per silent site per year, our results indicate that the D. melanogaster lineage split from D. yakuba approximately 5.1 +/- 0.8 million years ago (mya), D. mauritiana 2.7 +/- 0.4 mya, and D. simulans 2.3 +/- 0.3 mya. It implies that D. melanogaster became distinct from D. mauritiana and D. simulans at approximately the same time and from D. yakuba no earlier than 10 mya. The effective ancestral population size of D. melanogaster appears to be stable over evolutionary time. Assuming 10 generations per year for Drosophila, the effective population size in the ancestral lineage immediately prior to the time of species divergence is approximately 3 x 10(6), which is close to that estimated for the extant D. melanogaster population. The D. melanogaster did not encounter any obvious bottleneck during the past 10 million years.

Research paper thumbnail of NOS2A and the modulating effect of cigarette smoking in Parkinson's disease

Annals of Neurology, 2006

ObjectiveInducible nitric oxide synthase, a protein product of NOS2A, generates nitric oxide as a... more ObjectiveInducible nitric oxide synthase, a protein product of NOS2A, generates nitric oxide as a defense mechanism, but excessive levels threaten cellular survival. NOS2A is a candidate gene for Parkinson's disease (PD) that potentially interacts with cigarette smoking. We examined NOS2A for association with PD risk and age at onset (AAO) and for interaction with smoking.Inducible nitric oxide synthase, a protein product of NOS2A, generates nitric oxide as a defense mechanism, but excessive levels threaten cellular survival. NOS2A is a candidate gene for Parkinson's disease (PD) that potentially interacts with cigarette smoking. We examined NOS2A for association with PD risk and age at onset (AAO) and for interaction with smoking.MethodsWe genotyped 13 NOS2A single nucleotide polymorphisms (SNPs) in 466 singleton families and in a validation set of 286 multiplex families. We tested allelic and haplotypic association using the association in the presence of linkage test, genotypic associations using the genotype pedigree disequilibrium test, AAO effects using the quantitative transmission disequilibrium test, and interactions using generalized estimating equations.We genotyped 13 NOS2A single nucleotide polymorphisms (SNPs) in 466 singleton families and in a validation set of 286 multiplex families. We tested allelic and haplotypic association using the association in the presence of linkage test, genotypic associations using the genotype pedigree disequilibrium test, AAO effects using the quantitative transmission disequilibrium test, and interactions using generalized estimating equations.ResultsAmong the pooled earliest onset families, rs2255929 and rs1060826 generated significant allelic (p = 0.000059 and 0.0062, respectively) and genotypic (p = 0.0039 and 0.0014, respectively) associations with risk and AAO (p = 0.00070 and 0.0073, respectively); the two-SNP haplotype generated even stronger association with PD (p = 0.000013). Significant interactions with smoking (p = 0.0015 for rs 2255929 and p < 0.0001 for rs 1060826) were detected in a subset of the families; smoking was inversely associated with PD among risk allele noncarriers, but significance diminished among carriers.Among the pooled earliest onset families, rs2255929 and rs1060826 generated significant allelic (p = 0.000059 and 0.0062, respectively) and genotypic (p = 0.0039 and 0.0014, respectively) associations with risk and AAO (p = 0.00070 and 0.0073, respectively); the two-SNP haplotype generated even stronger association with PD (p = 0.000013). Significant interactions with smoking (p = 0.0015 for rs 2255929 and p < 0.0001 for rs 1060826) were detected in a subset of the families; smoking was inversely associated with PD among risk allele noncarriers, but significance diminished among carriers.InterpretationOur findings support NOS2A as a genetic risk factor in PD, potentially by influencing AAO and by modifying the inverse association between PD and smoking. Ann Neurol 2006Our findings support NOS2A as a genetic risk factor in PD, potentially by influencing AAO and by modifying the inverse association between PD and smoking. Ann Neurol 2006

Research paper thumbnail of Genomic convergence to identify candidate genes for Parkinson disease: SAGE analysis of the substantia nigra

Movement Disorders, 2005

Genomic convergence is a multistep approach that combines gene expression with genomic linkage to... more Genomic convergence is a multistep approach that combines gene expression with genomic linkage to identify and prioritize susceptibility genes for complex disease. As a first step, we previously performed linkage analysis on 174 multiplex Parkinson's disease (PD) families, identifying five peaks for PD risk and two for genes affecting age at onset (AAO) in PD [Hauser et al., Hum Mol Genet 2003;12:671–677]. We report here the next step: serial analysis of gene expression [SAGE; Scott et al., JAMA 2001;286:2239–2242] to analyze substantia nigra tissue from three PD patients and two age-matched controls. We find 933 differentially expressed genes (P < 0.05) between PD and controls, but of these, only 50 genes represented by unique SAGE tags map within our previously described PD linkage regions. Furthermore, genes encoded by mitochondrial DNA are expressed 1.5-fold higher in PD patients versus controls, without an increase in the corresponding nuclear-encoded mitochondrial components, suggesting an increase in mtDNA genomes in PD or a disjunction with nuclear expression. The next step in the genomic convergence process will be to screen these 50 high-quality candidate genes for association with PD risk susceptibility and genetic effects on AAO. © 2005 Movement Disorder Society

Research paper thumbnail of Methods for interaction analyses using family-based case-control data: conditional logistic regression versus generalized estimating equations

Genetic Epidemiology, 2007

A complex web of gene-gene and gene-environment interactions likely underlies late-onset disease ... more A complex web of gene-gene and gene-environment interactions likely underlies late-onset disease development. We compared conditional logistic regression (CLR) and generalized estimating equations (GEE) in modeling such interactions in pedigrees with missing parents. Using the simulation of linkage and association (SIMLA) program, disease genes, an environmental risk factor, gene-gene interaction, and gene-environment interaction were generated in family-based data sets. Four scenarios for the relationship between the marker and disease loci were examined: linkage and association, linkage without association, association without linkage, and absence of both linkage and association. Models for CLR and GEE (with exchangeable and independence correlation matrices) were built, and type I error, power, average odds ratio (OR), standard deviation, and 95% confidence intervals were estimated. CLR and GEE were valid tests of association in the presence of linkage, but type I error was inflated for association without linkage, particularly with GEE. CLR generated estimates of the OR with lower bias but often more variability than the OR estimates observed for GEE. Further, GEE was more powerful than CLR in detecting main and interactive effects. Although GEE with both matrices had similar power, use of the independence matrix resulted in lower type I error and less biased OR estimation as compared to the exchangeable matrix. Our findings support the use of GEE in maximizing power to detect gene-gene and gene-environment interactions but caution its use under potential association without linkage (e.g., population stratification) and the interpretation of its OR estimates. Genet. Epidemiol. 2007. © 2007 Wiley-Liss, Inc.

Research paper thumbnail of Expression Profiling of Substantia Nigra in Parkinson Disease, Progressive Supranuclear Palsy, and Frontotemporal Dementia With Parkinsonism

Archives of Neurology, 2005

Parkinson disease (PD) is characterized by loss of dopaminergic neurons in the substantia nigra. ... more Parkinson disease (PD) is characterized by loss of dopaminergic neurons in the substantia nigra. Genes contributing to rare mendelian forms of PD have been identified, but the genes involved in the more common idiopathic PD are not well understood. To identify genes important to PD pathogenesis using microarrays and to investigate their potential to aid in diagnosing parkinsonism. Microarray expression analysis of postmortem substantia nigra tissue. Substantia nigra samples from 14 unrelated individuals were analyzed, including 6 with PD, 2 with progressive supranuclear palsy, 1 with frontotemporal dementia with parkinsonism, and 5 control subjects. Identification of genes significantly differentially expressed (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;.05) using Affymetrix U133A microarrays. There were 142 genes that were significantly differentially expressed between PD cases and controls and 96 genes that were significantly differentially expressed between the combined progressive supranuclear palsy and frontotemporal dementia with parkinsonism cases and controls. The 12 genes common to all 3 disorders may be related to secondary effects. Hierarchical cluster analysis after exclusion of these 12 genes differentiated 4 of the 6 PD cases from progressive supranuclear palsy and frontotemporal dementia with parkinsonism. Four main molecular pathways are altered in PD substantia nigra: chaperones, ubiquitination, vesicle trafficking, and nuclear-encoded mitochondrial genes. These results correlate well with expression analyses performed in several PD animal models. Expression analyses have promising potential to aid in postmortem diagnostic evaluation of parkinsonism.

Research paper thumbnail of Identification of Risk and Age-at-Onset Genes on Chromosome 1p in Parkinson Disease

American Journal of Human Genetics, 2005

We previously reported a linkage region on chromosome 1p (LOD p 3.41) for genes controlling age a... more We previously reported a linkage region on chromosome 1p (LOD p 3.41) for genes controlling age at onset (AAO) in Parkinson disease (PD). This region overlaps with the previously reported PARK10 locus. To identify the gene(s) associated with AAO and risk of PD in this region, we first applied a genomic convergence approach that combined gene expression and linkage data. No significant results were found. Second, we performed association mapping across a 19.2-Mb region centered under the AAO linkage peak. An iterative association mapping approach was done by initially genotyping single-nucleotide polymorphisms at an average distance of 100 kb apart and then by increasing the density of markers as needed. Using the overall data set of 267 multiplex families, we identified six associated genes in the region, but further screening of a subset of 83 families linked to the chromosome 1 locus identified only two genes significantly associated with AAO in PD: the g subunit of the translation initiation factor EIF2B gene (EIF2B3), which was more significant in the linked subset and the ubiquitin-specific protease 24 gene (USP24). Unexpectedly, the human immunodeficiency virus enhancer-binding protein 3 gene (HIVEP3) was found to be associated with risk for susceptibility to PD. We used several criteria to define significant results in the presence of multiple testing, including criteria derived from a novel cluster approach. The known or putative functions of these genes fit well with the current suspected pathogenic mechanisms of PD and thus show great potential as candidates for the PARK10 locus.

Research paper thumbnail of Genome-wide Association Study Implicates a Chromosome 12 Risk Locus for Late-Onset Alzheimer Disease

American Journal of Human Genetics, 2009

Many candidate genes have been studied for asthma, but replication has varied. Novel candidate ge... more Many candidate genes have been studied for asthma, but replication has varied. Novel candidate genes have been identified for various complex diseases using genome-wide association studies (GWASs). We conducted a GWAS in 492 Mexican children with asthma, predominantly atopic by skin prick test, and their parents using the Illumina HumanHap 550 K BeadChip to identify novel genetic variation for childhood asthma. The 520,767 autosomal single nucleotide polymorphisms (SNPs) passing quality control were tested for association with childhood asthma using log-linear regression with a log-additive risk model. Eleven of the most significantly associated GWAS SNPs were tested for replication in an independent study of 177 Mexican case-parent trios with childhood-onset asthma and atopy using log-linear analysis. The chromosome 9q21.31 SNP rs2378383 (p = 7.10610 26 in the GWAS), located upstream of transducin-like enhancer of split 4 (TLE4), gave a p-value of 0.03 and the same direction and magnitude of association in the replication study (combined p = 6.79610 27 ). Ancestry analysis on chromosome 9q supported an inverse association between the rs2378383 minor allele (G) and childhood asthma. This work identifies chromosome 9q21.31 as a novel susceptibility locus for childhood asthma in Mexicans. Further, analysis of genome-wide expression data in 51 human tissues from the Novartis Research Foundation showed that median GWAS significance levels for SNPs in genes expressed in the lung differed most significantly from genes not expressed in the lung when compared to 50 other tissues, supporting the biological plausibility of our overall GWAS findings and the multigenic etiology of childhood asthma.