Biological interpretation of genome-wide association studies using predicted gene functions

Pers, Tune H.; Karjalainen, Juha; Chan, Yingleong; Westra, Harm-Jan; Wood, Andrew R.; Yang, Jian; Lui, Julian C.; Vedantam, Sailaja; Gustafsson, Stefan; Esko, Tõnu; Frayling, Tim; Speliotes, Elizabeth K.; Boehnke, Michael; Raychaudhuri, Soumya; Fehrmann, Rudolf S.N.; Hirschhorn, Joel N.; Franke, Lude

doi:10.1038/ncomms6890

Cited by 777 publications

(956 citation statements)

References 36 publications

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“…We used DEPICT 22 to link genome-wide significant hits to candidate genes (Supplementary Table 10 and Supplementary Notes) and, within each GWAS-derived gene set, we studied the association between rare PTVs and the phenotypes using the SKAT test. GWAS-derived gene-sets captured associations between rare PTVs and different classes of lipids (Figure 3 and Supplementary Table 11).…”

Section: Introductionmentioning

confidence: 99%

Quantifying the impact of rare and ultra-rare coding variation across the phenotypic spectrum

Ganna

Satterstrom

Zekavat

et al. 2017

Preprint

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There is a limited understanding about the impact of rare protein truncating variants across multiple phenotypes. We explore the impact of this class of variants on 13 quantitative traits and 10 diseases using whole-exome sequencing data from 100,296 individuals. Protein truncating variants in genes intolerant to this class of mutations increased risk of autism, schizophrenia, bipolar disorder, intellectual disability, ADHD. In individuals without these disorders, there was an association with shorter height, lower education, increased hospitalization and reduced age. Gene sets implicated from GWAS did not show a significant protein truncating variants-burden beyond what captured by established Mendelian genes. In conclusion, we provide the most thorough investigation to date of the impact of rare deleterious coding variants on complex traits, suggesting widespread pleiotropic risk.Main abbreviationsPTV= Protein Truncating VariantsPI= Protein Truncating IntolerantPI-PTV= Protein Truncating Variant in genes that are Intolerant to Protein Truncating Variants

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Section: Introductionmentioning

confidence: 99%

Quantifying the impact of rare and ultra-rare coding variation across the phenotypic spectrum

Ganna

Satterstrom

Zekavat

et al. 2017

Preprint

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“…Two other significant tissues were from the digestive system; esophagus muscularis and esophageal mucosa. We replicated these enrichment results in an independent dataset using a component of the DEPICT 66 tool that conducts a tissue-specific enrichment analysis on microarray-based gene expression data (Supplementary Methods). DEPICT highlighted four tissues (Figure 3 and Supplementary Table 13) with significant enrichment of the genes within the migraine loci; arteries (P = 1.58 × 10 -5 ), the upper gastrointestinal tract (P = 2.97 × 10 -3 ), myometrium (P = 3.03 × 10 -3 ), and stomach (P = 3.38 × 10 -3 ).…”

Section: Gene Expression Enrichment In Specific Tissuesmentioning

confidence: 78%

“…For a comprehensive pathway analysis tool we used DEPICT, which incorporates co-expression information from gene expression microarray data to implicate additional, functionally less wellcharacterized genes in known biological pathways, protein-protein complexes and mouse phenotypes 66 (by forming so-called 'reconstituted gene sets'). From DEPICT we identified 67 reconstituted gene sets that are significantly enriched (FDR < 5%) for genes found among the 38 migraine associated loci (Supplementary Table 16 Figure 5 and Supplementary Table 16).…”

Section: Gene Set Enrichment Analyzesmentioning

confidence: 99%

Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine

Gormley

Anttila

Winsvold

et al. 2015

Preprint

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Migraine is a debilitating neurological disorder affecting around 1 in 7 people worldwide, but its molecular mechanisms remain poorly understood. Some debate exists over whether migraine is a disease of vascular dysfunction, or a result of neuronal dysfunction with secondary vascular changes. Genome-wide association (GWA) studies have thus far identified 13 independent loci associated with migraine. To identify new susceptibility loci, we performed the largest genetic study of migraine to date, comprising 59,674 cases and 316,078 controls from 22 GWA studies. We identified 45 independent single nucleotide polymorphisms (SNPs) significantly associated with migraine risk (P < 5 x 10-8) that map to 38 distinct genomic loci, including 28 loci not previously reported and the first locus identified on chromosome X. Furthermore, a subset analysis for migraine without aura (MO) identified seven of the same loci as from the full sample, whereas no loci reached genome-wide significance in the migraine with aura (MA) subset. In subsequent computational analyzes, the identified loci showed enrichment for genes expressed in vascular and smooth muscle tissues, consistent with a predominant theory of migraine that highlights vascular etiologies.

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“…We used several bioinformatics approaches (LDlink,30 RegulomeDB,31 Genome‐Wide Annotation of Variants [GWAVA],32 and Data‐driven Expression Prioritized Integration for Complex Traits [DEPICT]33) to search and annotate SNPs in the regions containing genome‐wide significant SNPs. Publicly available reference haplotypes from Phase 3 (Version 5) of the 1000 Genomes Project (1000G)34 were used to calculate population‐specific measures of linkage disequilibrium (LD)30 in whites.…”

Section: Methodsmentioning

confidence: 99%

Genome‐Wide Associations of Global Electrical Heterogeneity ECG Phenotype: The ARIC (Atherosclerosis Risk in Communities) Study and CHS (Cardiovascular Health Study)

Tereshchenko

Sotoodehnia

Sitlani

et al. 2018

JAHA

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Background ECG global electrical heterogeneity (GEH) is associated with sudden cardiac death. We hypothesized that a genome‐wide association study would identify genetic loci related to GEH.Methods and ResultsWe tested genotyped and imputed variants in black (N=3057) and white (N=10 769) participants in the ARIC (Atherosclerosis Risk in Communities) study and CHS (Cardiovascular Health Study). GEH (QRS‐T angle, sum absolute QRST integral, spatial ventricular gradient magnitude, elevation, azimuth) was measured on 12‐lead ECGs. Linear regression models were constructed with each GEH variable as an outcome, adjusted for age, sex, height, body mass index, study site, and principal components to account for ancestry. GWAS identified 10 loci that showed genome‐wide significant association with GEH in whites or joint ancestry. The strongest signal (rs7301677, near TBX3) was associated with QRS‐T angle (white standardized β+0.16 [95% CI 0.13–0.19]; P=1.5×10−26), spatial ventricular gradient elevation (+0.11 [0.08–0.14]; P=2.1×10−12), and spatial ventricular gradient magnitude (−0.12 [95% CI −0.15 to −0.09]; P=5.9×10−15). Altogether, GEH‐SNPs explained 1.1% to 1.6% of GEH variance. Loci on chromosomes 4 (near HMCN2), 5 (IGF1R), 11 (11p11.2 region cluster), and 7 (near ACTB) are novel ECG phenotype‐associated loci. Several loci significantly associated with gene expression in the left ventricle (HMCN2 locus—with HMCN2;IGF1R locus—with IGF1R), and atria (RP11‐481J2.2 locus—with expression of a long non‐coding RNA and NDRG4).ConclusionsWe identified 10 genetic loci associated with ECG GEH. Replication of GEH GWAS findings in independent cohorts is warranted. Further studies of GEH‐loci may uncover mechanisms of arrhythmogenic remodeling in response to cardiovascular risk factors.

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Biological interpretation of genome-wide association studies using predicted gene functions

Cited by 777 publications

References 36 publications

Quantifying the impact of rare and ultra-rare coding variation across the phenotypic spectrum

Quantifying the impact of rare and ultra-rare coding variation across the phenotypic spectrum

Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine

Genome‐Wide Associations of Global Electrical Heterogeneity ECG Phenotype: The ARIC (Atherosclerosis Risk in Communities) Study and CHS (Cardiovascular Health Study)

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