Partitioning heritability by functional annotation using genome-wide association summary statistics

Finucane, Hilary; Bulik-Sullivan, Brendan; Gusev, Alexander; Trynka, Gosia; Reshef, Yakir; Loh, Po−Ru; Anttila, Vesa; Han, Xu; Zang, Chongzhi; Farh, Kyle Kai How; Ripke, Stephan; Day, Felix R.; Purcell, Shaun; Stahl, Eli A.; Lindström, Sara; Perry, John R. B.; Okada, Yukinori; Raychaudhuri, Soumya; Daly, Mark J.; Patterson, Nick; Neale, Benjamin M.; Price, Alkes L.

doi:10.1038/ng.3404

Cited by 2,356 publications

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“…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. LD score regression exploits the expected relationships between true association signals and local LD around them to correct out systematic biases and arrive at unbiased estimates of genetic heritability within a given set of SNPs (here stratified according to their functional category) 31. Following Finucane et al,31 we added annotations individually to the baseline model; we used HapMap Project Phase 3 SNPs for the regression and 1000 Genomes Project European population SNPs for the reference panel; we only partitioned the heritability of SNPs with minor allele frequency >5%; and we excluded the Major Histocompatibility Complex (MHC) region from analysis.…”

Section: Methodsmentioning

confidence: 99%

“…LD score regression exploits the expected relationships between true association signals and local LD around them to correct out systematic biases and arrive at unbiased estimates of genetic heritability within a given set of SNPs (here stratified according to their functional category) 31. Following Finucane et al,31 we added annotations individually to the baseline model; we used HapMap Project Phase 3 SNPs for the regression and 1000 Genomes Project European population SNPs for the reference panel; we only partitioned the heritability of SNPs with minor allele frequency >5%; and we excluded the Major Histocompatibility Complex (MHC) region from analysis. The high LD and strong association signals within the MHC region results in a dominating effect on LD score regression, and for the purposes of our analyses excluding this region result in a conservative approach.…”

Section: Methodsmentioning

confidence: 99%

“…The grouped cell‐type annotations provided by Finucane et al31 are the union of histone marks for 10 broad categories including central nervous system (CNS), cardiovascular, immune/hematopoietic, and liver. For these analyses, we corrected for multiple testing of four GWASs across 10 cell‐type groups (4 × 10 = 40 hypotheses tested), resulting in a Bonferroni significance threshold of P = 1.2 × 10 −3 .…”

Section: Methodsmentioning

confidence: 99%

“…Finucane et al31 introduced stratified LD score regression as a method for partitioning the inferred heritability from GWAS summary statistics. They determined whether genetic heritability in 17 GWASs was enriched within various functional annotations which reflected parts of the genome that were active in a number of tissues and cell types.…”

Section: Introductionmentioning

confidence: 99%

“…They determined whether genetic heritability in 17 GWASs was enriched within various functional annotations which reflected parts of the genome that were active in a number of tissues and cell types. We applied this methodology to four diseases (MS, AD, ALS, PD) to test for enrichment of heritability, both using Finucane et al's31 cell‐type group annotations and using additional annotations from brain and immune cells and from published sets of brain and immune‐related genes 32…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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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Distinct Genetic Risk Profile in Aortic Stenosis Compared With Coronary Artery Disease

Trenkwalder,

Maj,

Al-Kassou

et al. 2024

JAMA Cardiol

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ImportanceAortic stenosis (AS) and coronary artery disease (CAD) frequently coexist. However, it is unknown which genetic and cardiovascular risk factors might be AS-specific and which could be shared between AS and CAD.ObjectiveTo identify genetic risk loci and cardiovascular risk factors with AS-specific associations.Design, Setting, and ParticipantsThis was a genomewide association study (GWAS) of AS adjusted for CAD with participants from the European Consortium for the Genetics of Aortic Stenosis (EGAS) (recruited 2000-2020), UK Biobank (recruited 2006-2010), Estonian Biobank (recruited 1997-2019), and FinnGen (recruited 1964-2019). EGAS participants were collected from 7 sites across Europe. All participants were of European ancestry, and information on comorbid CAD was available for all participants. Follow-up analyses with GWAS data on cardiovascular traits and tissue transcriptome data were also performed. Data were analyzed from October 2022 to July 2023.ExposuresGenetic variants.Main Outcomes and MeasuresCardiovascular traits associated with AS adjusted for CAD. Replication was performed in 2 independent AS GWAS cohorts.ResultsA total of 18 792 participants with AS and 434 249 control participants were included in this GWAS adjusted for CAD. The analysis found 17 AS risk loci, including 5 loci with novel and independently replicated associations (RNF114A, AFAP1, PDGFRA, ADAMTS7, HAO1). Of all 17 associated loci, 11 were associated with risk specifically for AS and were not associated with CAD (ALPL, PALMD, PRRX1, RNF144A, MECOM, AFAP1, PDGFRA, IL6, TPCN2, NLRP6, HAO1). Concordantly, this study revealed only a moderate genetic correlation of 0.15 (SE, 0.05) between AS and CAD (P = 1.60 × 10−3). Mendelian randomization revealed that serum phosphate was an AS-specific risk factor that was absent in CAD (AS: odds ratio [OR], 1.20; 95% CI, 1.11-1.31; P = 1.27 × 10−5; CAD: OR, 0.97; 95% CI 0.94-1.00; P = .04). Mendelian randomization also found that blood pressure, body mass index, and cholesterol metabolism had substantially lesser associations with AS compared with CAD. Pathway and transcriptome enrichment analyses revealed biological processes and tissues relevant for AS development.Conclusions and RelevanceThis GWAS adjusted for CAD found a distinct genetic risk profile for AS at the single-marker and polygenic level. These findings provide new targets for future AS research.

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Association of Essential Tremor With Novel Risk Loci

et al. 2022

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IMPORTANCE Essential tremor (ET) is one of the most common movement disorders, affecting 5% of the general population older than 65 years. Common variants are thought to contribute toward susceptibility to ET, but no variants have been robustly identified. OBJECTIVE To identify common genetic factors associated with risk of ET. DESIGN, SETTING, AND PARTICIPANTS Case-control genome-wide association study. Inverse-variance meta-analysis was used to combine cohorts. Multicenter samples collected from European populations were collected from January 2010 to September 2019 as part of an ongoing study. Included patients were clinically diagnosed with or reported having ET. Control individuals were not diagnosed with or reported to have ET. Of 485 250 individuals, data for 483 054 passed data quality control and were used. MAIN OUTCOMES AND MEASURES Genotypes of common variants associated with risk of ET. RESULTS Of the 483 054 individuals included, there were 7177 with ET (3693 [51.46%] female; mean [SD] age, 62.66 [15.12] years), and 475 877 control individuals (253 785 [53.33%] female; mean [SD] age, 56.40 [17.6] years). Five independent genome-wide significant loci and were identified and were associated with approximately 18% of ET heritability. Functional analyses found significant enrichment in the cerebellar hemisphere, cerebellum, and axonogenesis pathways. Genetic correlation (r), which measures the degree of genetic overlap, revealed significant common variant overlap with Parkinson disease (r, 0.28; P = 2.38 × 10 −8 ) and depression (r, 0.12; P = 9.78 × 10 −4 ). A separate fine-mapping of transcriptome-wide association hits identified genes such as BACE2, LRRN2, DHRS13, and LINC00323 in disease-relevant brain regions, such as the cerebellum. CONCLUSIONS AND RELEVANCEThe results of this genome-wide association study suggest that a portion of ET heritability can be explained by common genetic variation and can help identify new common genetic risk factors for ET.

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Partitioning heritability by functional annotation using genome-wide association summary statistics

Cited by 2,356 publications

References 50 publications

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

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

Distinct Genetic Risk Profile in Aortic Stenosis Compared With Coronary Artery Disease

Association of Essential Tremor With Novel Risk Loci

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