Data analysis in the post-genome-wide association study era (original) (raw)
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BMC Research Notes, 2010
Background: Substantial genotyping data produced by current high-throughput technologies have brought opportunities and difficulties. With the number of single-nucleotide polymorphisms (SNPs) going into millions comes the harsh challenge of multiple-testing adjustment. However, even with the false discovery rate (FDR) control approach, a genome-wide association study (GWAS) may still fall short of discovering any true positive gene, particularly when it has a relatively small sample size. Findings: To counteract such a harsh multiple-testing penalty, in this report, we incorporate findings from previous linkage and association studies to re-analyze a GWAS on age-related macular degeneration. While previous Bonferroni correction and the traditional FDR approach detected only one significant SNP (rs380390), here we have been able to detect seven significant SNPs with an easy-to-implement prioritized subset analysis (PSA) with the overall FDR controlled at 0.05. These include SNPs within three genes: CFH, CFHR4, and SGCD. Conclusions: Based on the success of this example, we advocate using the simple method of PSA to facilitate discoveries in future GWASs.
Scientific Reports, 2015
Age-related macular degeneration (AMD), a multifactorial, neurodegenerative disease, is a leading cause of vision loss. With the rapid advancement of DNA sequencing technologies, many AMDassociated genetic polymorphisms have been identified. Currently, the most time consuming steps of these studies are patient recruitment and phenotyping. In this study, we describe the development of an automated algorithm to identify neovascular (wet) AMD, non-neovascular (dry) AMD and control subjects using electronic medical record (EMR)-based criteria. Positive predictive value (91.7%) and negative predictive value (97.5%) were calculated using expert chart review as the gold standard to assess algorithm performance. We applied the algorithm to an EMR-linked DNA bio-repository to study previously identified AMD-associated single nucleotide polymorphisms (SNPs), using case/ control status determined by the algorithm. Risk alleles of three SNPs, rs1061170 (CFH), rs1410996 (CFH), and rs10490924 (ARMS2) were found to be significantly associated with the AMD case/control status as defined by the algorithm. With the rapid growth of EMR-linked DNA biorepositories, patient selection algorithms can greatly increase the efficiency of genetic association study. We have found that stepwise validation of such an algorithm can result in reliable cohort selection and, when coupled within an EMR-linked DNA biorepository, replicates previously published AMD-associated SNPs. Age-related macular degeneration (AMD) is a multifactorial neurodegenerative disease that is the leading cause of blindness in western individuals over the age of 65 1-4. Clinical presentation of AMD is heterogeneous, with many genetic and environmental risk factors contributing to its pathogenesis 5. The rate of identification of AMD-associated genetic risk factors, including but not limited to single nucleotide polymorphisms (SNPs) in CFH, ARMS2 and HTRA1 genes, has increased rapidly with the utilization of genome-wide association studies (GWAS) 6-9. These studies have led to a better understanding of AMD pathophysiology, creation of genetic based prediction models and a plethora of AMD pharmacogenomics studies 8,10-15. GWAS studies have also identified environmental exposures that interact with AMD genetic risk factors, highlighting the importance of developing accurate criteria for clinical phenotyping in order to discriminate disease and control populations 16,17. One important barrier to genetic association
Ophthalmology, 2017
Age-related macular degeneration (AMD), a multifactorial disease with variable phenotypic presentation, was associated with 52 single nucleotide polymorphisms (SNPs) at 34 loci in a genome-wide association study (GWAS). These genetic variants could modulate different biological pathways involved in AMD, contributing to phenotypic variability. To better understand the effects of these SNPs, we performed a deep phenotype association study (DeePAS) in the Age-Related Eye Disease Study 2 (AREDS2), followed by replication using AREDS participants, to identify genotype associations with AMD and non-AMD ocular and systemic phenotypes. Cohort study. AREDS and AREDS2 participants. AREDS2 participants (discovery cohort) had detailed phenotyping for AMD; other eye conditions; cardiovascular, neurologic, gastrointestinal, and endocrine disease; cognitive function; serum nutrient levels; and others (total of 139 AMD and non-AMD phenotypes). Genotypes of the 52 GWAS SNPs were obtained. The DeePAS...
Scientific Reports
Genome-wide association studies (GWAS) for late stage age-related macular degeneration (AMD) have identified 52 independent genetic variants with genome-wide significance at 34 genomic loci. Typically, such an approach rarely results in the identification of functional variants implicating a defined gene in the disease process. We now performed a transcriptome-wide association study (TWAS) allowing the prediction of effects of AMD-associated genetic variants on gene expression. The TWAS was based on the genotypes of 16,144 late-stage AMD cases and 17,832 healthy controls, and gene expression was imputed for 27 different human tissues which were obtained from 134 to 421 individuals. A linear regression model including each individuals imputed gene expression data and the respective AMD status identified 106 genes significantly associated to AMD variants in at least one tissue (Q-value
Nature genetics, 2011
Age-related macular degeneration (AMD), the leading cause of irreversible blindness in the world, is a complex disease caused by multiple environmental and genetic risk factors. To identify genetic factors that modify the risk of exudative AMD in the Japanese population, we conducted a genome-wide association study and a replication study using a total of 1,536 individuals with exudative AMD and 18,894 controls. In addition to CFH (rs800292, P = 4.23 × 10(-15)) and ARMS2 (rs3750847, P = 8.67 × 10(-29)) loci, we identified two new susceptibility loci for exudative AMD: TNFRSF10A-LOC389641 on chromosome 8p21 (rs13278062, combined P = 1.03 × 10(-12), odds ratio = 0.73) and REST-C4orf14-POLR2B-IGFBP7 on chromosome 4q12 (rs1713985, combined P = 2.34 × 10(-8), odds ratio = 1.30). Fine mapping revealed that rs13278062, which is known to alter TNFRSF10A transcriptional activity, had the most significant association in 8p21 region. Our results provide new insights into the pathophysiology of...
ABSTRACTBackgroundAdvanced age-related macular degeneration (AMD) is a leading cause of blindness. While around half of the genetic contribution to advanced AMD has been uncovered, little is known about the genetic architecture of the preceding early stages of the diseases.MethodsTo identify genetic factors for early AMD, we conducted a genome-wide association meta-analysis with 14,034 early AMD cases and 91,214 controls from 11 sources of data including data from the International AMD Genomics Consortium (IAMDGC) and the UK Biobank (UKBB). We ascertained early AMD via color fundus photographs by manual grading for 10 sources and by using an automated machine learning approach for >170,000 images from UKBB. We searched for significant genetic loci in a genome-wide association screen (P<5×10-8) based on the meta-analysis of the 11 sources and via a candidate approach based on 13 suggestive early AMD variants from Holliday et al 2013 (P<0.05/13, additional 3,432 early AMD cas...
PLoS ONE, 2013
Genetic factors explain a majority of risk variance for age-related macular degeneration (AMD). While genome-wide association studies (GWAS) for late AMD implicate genes in complement, inflammatory and lipid pathways, the genetic architecture of early AMD has been relatively under studied. We conducted a GWAS meta-analysis of early AMD, including 4,089 individuals with prevalent signs of early AMD (soft drusen and/or retinal pigment epithelial changes) and 20,453 individuals without these signs. For various published late AMD risk loci, we also compared effect sizes between early and late AMD using an additional 484 individuals with prevalent late AMD. GWAS meta-analysis confirmed previously reported association of variants at the complement factor H (CFH) (peak P = 1.5610 231 ) and age-related maculopathy susceptibility 2 (ARMS2) (P = 4.3610 224 ) loci, and suggested Apolipoprotein E (ApoE) polymorphisms (rs2075650; P = 1.1610 26 ) associated with early AMD. Other possible loci that did not reach GWAS significance included variants in the zinc finger protein gene GLI3 (rs2049622; P = 8.9610 26 ) and upstream of GLI2 (rs6721654; P = 6.5610 26 ), encoding retinal Sonic hedgehog signalling regulators, and in the tyrosinase (TYR) gene (rs621313; P = 3.5610 26 ), involved in melanin biosynthesis. For a range of published, late AMD risk loci, estimated effect sizes were significantly lower for early than late AMD. This study confirms the involvement of multiple established AMD risk variants in early AMD, but suggests weaker genetic effects on the risk of early AMD relative to late AMD. Several biological processes were suggested to be potentially specific for early AMD, including pathways regulating RPE cell melanin content and signalling pathways potentially involved in retinal regeneration, generating hypotheses for further investigation.
Ophthalmology, 2012
Hair color is one of the most visible and heritable traits in humans. Here, we estimated heritability by structural equation modeling (N = 20,142), and performed a genome wide association (GWA) analysis (N = 7091) and a GCTA study (N = 3340) on hair color within a large cohort of twins, their parents and siblings from the Netherlands Twin Register (NTR). Self-reported hair color was analyzed as five binary phenotypes, namely "blond versus non-blond", "red versus non-red", "brown versus non-brown", "black versus non-black", and "light versus dark". The broad-sense heritability of hair color was estimated between 73% and 99% and the genetic component included non-additive genetic variance. Assortative mating for hair color was significant, except for red and black hair color. From GCTA analyses, at most 24.6% of the additive genetic variance in hair color was explained by 1000G well-imputed SNPs. Genome-wide association analysis for each hair color showed that SNPs in the MC1R region were significantly associated with red, brown and black hair, and also with light versus dark hair color. Five other known genes (HERC2, TPCN2, SLC24A4, IRF4, and KITLG) gave genome-wide significant hits for blond, brown and light versus dark hair color. We did not find and replicate any new loci for hair color.
Seven new loci associated with age-related macular degeneration
Nature Genetics, 2013
Age-related macular degeneration (AMD) is a common cause of blindness in older individuals. To accelerate understanding of AMD biology and help design new therapies, we executed a collaborative genomewide association study, examining >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry. We identified 19 genomic loci associated with AMD with p<5×10 −8 and enriched for genes involved in regulation of complement activity, lipid metabolism, extracellular matrix remodeling and angiogenesis. Our results include 7 loci reaching p<5×10 −8 for the first time, near the genes COL8A1/FILIP1L, IER3/DDR1, SLC16A8, TGFBR1, RAD51B, ADAMTS9/MIR548A2, and B3GALTL. A genetic risk score combining SNPs from all loci displayed similar good ability to distinguish cases and controls in all samples examined. Our findings provide new directions for biological, genetic and therapeutic studies of AMD. AMD is a highly heritable progressive neurodegenerative disease that leads to loss of central vision through death of photoreceptors 1,2. In developed countries, AMD is the leading cause of blindness in those >65 years 3. Genes in the complement pathway 4-11 and a region of chromosome 10 12,13 have now been implicated as the major genetic contributors to disease. Association has also been demonstrated with several additional loci 14-20 , each providing an entry-point into AMD biology and potential therapeutic targets. To accelerate the pace of discovery in macular degeneration genetics, 18 research groups from across the world formed the AMD Gene Consortium in early 2010, with support from the National Eye Institute (Table 1, Supplementary Table 1, Supplementary Note). To extend the catalog of disease associated common variants, we first organized a meta-analysis of genomewide association scans (GWAS)-combining data for >7,600 cases with advanced disease (geographic atrophy, neovascularization, or both) and >50,000 controls. Each study was first subject to GWAS quality control filters (customized taking into account study specific features 21 as detailed in Supplementary Table 2) and standardized to the HapMap reference panel and statistical genotype imputation 22-25. Results were combined through meta-analysis 26 and thirty-two variants representing loci with promising evidence of association were genotyped in an additional >9,500 cases and >8,200 controls Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: