An atlas of genetic correlations across human diseases and traits

Bulik-Sullivan, Brendan; Finucane, Hilary; Anttila, Verneri; Gusev, Alexander; Day, Felix R.; Loh, Po−Ru; Duncan, Laramie; Perry, John R. B.; Patterson, Nick; Robinson, Elise; Daly, Mark J.; Price, Alkes L.; Neale, Benjamin M.

doi:10.1038/ng.3406

Cited by 3,532 publications

(2,832 citation statements)

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“…Prior work attempting to catalog the prevalence of pleiotropy in the human genome has suggested that pleiotropy is common, but the scope of earlier studies was limited by the number of phenotypes investigated (≤ 53 phenotypes) (Bulik-Sullivan et al 2015;Pickrell et al 2016;Visscher and Yang 2016). We expand upon these prior findings by investigating all 1094 phenotypes listed in the GWAS catalog as of mid-2017.…”

Section: Discussionmentioning

confidence: 93%

The ubiquity of pleiotropy in human disease

2017

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Pleiotropy has long been thought to be a common phenomenon in the human genome; however, until recently appropriate data was unavailable to test this hypothesis. Prior studies focused on assessing the prevalence of pleiotropy in only small subsets of phenotypes (≤ 53 phenotypes), without a truly comprehensive assessment of pleiotropy in the human genome. In this study, we determined the prevalence of pleiotropy, using the entire GWAS catalog (1094 disease phenotypes, 14,459 genes), as well as investigate the relationship between the degree of pleiotropy and the average effect size for each associating gene. The number of associating phenotypes per gene ranged from 1 to 53, with 44% of genes reported in the GWAS catalog associating with more than one phenotype. The proportion of genes shown to be pleiotropic has continued to increase as more studies are added to the catalog. We also found the degree of pleiotropy scales positively with a gene's average effect size (r = 0.04, p value = 0.0003) and negatively with the variance of effect sizes in genes with a given number of associating phenotypes (r = − 0.590, p value = 0.0019). Based on this and prior work, it is becoming evident that pleiotropy is a common, if not ubiquitous, phenomenon. These results have implications in understanding disease etiologies, potentially common biology underlying even disparate diseases, and in elucidating the genotype-phenotype map.

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Section: Discussionmentioning

confidence: 93%

The ubiquity of pleiotropy in human disease

2017

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“…This is an important consideration given that most SNPs discovered by GWAS across any phenotypes have small phenotypic consequences. Our limited power also prevents us from using sophisticated statistical methods, such as LD score regression, to estimate CEC heritability or genetic correlations with other complex human diseases and traits 38, 39. Given our limited power, future replication studies of our CEC associations should consider inflation of the estimated effect sizes because of the winner's curse.…”

Section: Discussionmentioning

confidence: 99%

Variants at the APOE/C1/C2/C4 Locus Modulate Cholesterol Efflux Capacity Independently of High‐Density Lipoprotein Cholesterol

Low‐Kam

Rhainds

et al. 2018

JAHA

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BackgroundMacrophage cholesterol efflux to high‐density lipoproteins (HDLs) is the first step of reverse cholesterol transport. The cholesterol efflux capacity (CEC) of HDL particles is a protective risk factor for coronary artery disease independent of HDL cholesterol levels. Using a genome‐wide association study approach, we aimed to identify pathways that regulate CEC in humans.Methods and ResultsWe measured CEC in 5293 French Canadians. We tested the genetic association between 4 CEC measures and genotypes at >9 million common autosomal DNA sequence variants. These analyses yielded 10 genome‐wide significant signals (P<6.25×10−9) representing 7 loci. Five of these loci harbor genes with important roles in lipid biology (CETP,LIPC,LPL,APOA1/C3/A4/A5, and APOE /C1/C2/C4). Except for the APOE/C1/C2/C4 variant (rs141622900, P nonadjusted=1.0×10−11; P adjusted=8.8×10−9), the association signals disappear when correcting for HDL cholesterol and triglyceride levels. The additional 2 significant signals were near the PPP1CB/PLB1 and RBFOX3/ENPP7 genes. In secondary analyses, we considered candidate functional variants for 58 genes implicated in HDL biology, as well as 239 variants associated with blood lipid levels and/or coronary artery disease risk by genome‐wide association study. These analyses identified 27 significant CEC associations, implicating 5 additional loci (GCKR,LIPG,PLTP,PPARA, and TRIB1).ConclusionsOur genome‐wide association study identified common genetic variation at the APOE/C1/C2/C4 locus as a major determinant of CEC that acts largely independently of HDL cholesterol. We predict that HDL‐based therapies aiming at increasing CEC will be modulated by changes in the expression of apolipoproteins in this gene cluster.

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“…Our findings further support the role of immune variation in AD susceptibility. Interestingly, using LD score regression, AD was found to be not significantly correlated with a variety of immune diseases 34. This lack of correlation could be because when considering the entire genome the signal coming from the correlated loci between the diseases is diluted, or the immune variants involved in AD are different from those involved in other immune diseases.…”

Section: Discussionmentioning

confidence: 99%

“…We estimated pairwise genetic correlations among the four diseases using cross‐trait LD score regression 34. We then applied stratified LD score regression to determine if various functional categories (cell‐type groups, annotations at the tissue/cell level for brain or immune cells, and sets of brain and immune gene lists) were enriched for heritability.…”

Section: Methodsmentioning

confidence: 99%

Genomics implicates adaptive and innate immunity in Alzheimer's and Parkinson's diseases

Gagliano

Pouget

Hardy

et al. 2016

Ann Clin Transl Neurol

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ObjectivesWe assessed the current genetic evidence for the involvement of various cell types and tissue types in the etiology of neurodegenerative diseases, especially in relation to the neuroinflammatory hypothesis of neurodegenerative diseases.MethodsWe obtained large‐scale genome‐wide association study (GWAS) summary statistics from Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). We used multiple sclerosis (MS), an autoimmune disease of the central nervous system, as a positive control. We applied stratified LD score regression to determine if functional marks for cell type and tissue activity, and gene‐set lists were enriched for genetic heritability. We compared our results to those from two gene‐set enrichment methods (Ingenuity Pathway Analysis and enrichr).ResultsThere were no significant heritability enrichments for annotations marking genes active within brain regions, but there were significant heritability enrichments for annotations marking genes active within cell types that form part of both the innate and adaptive immune systems. We found this for MS (as expected) and also for AD and PD. The strongest signals were from the adaptive immune system (e.g., T cells) for PD, and from both the adaptive (e.g., T cells) and innate (e.g., CD14: a marker for monocytes, and CD15: a marker for neutrophils) immune systems for AD. Annotations from the liver were also significant for AD. Pathway analysis provided complementary results.InterpretationFor AD and PD, we found significant enrichment of heritability in annotations marking gene activity in immune cells.

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An atlas of genetic correlations across human diseases and traits

Cited by 3,532 publications

References 62 publications

The ubiquity of pleiotropy in human disease

The ubiquity of pleiotropy in human disease

Variants at the APOE/C1/C2/C4 Locus Modulate Cholesterol Efflux Capacity Independently of High‐Density Lipoprotein Cholesterol

Genomics implicates adaptive and innate immunity in Alzheimer's and Parkinson's diseases

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