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

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

doi:10.1038/ng.3404

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

Hilary K. Finucane, Brendan Bulik-Sullivan, Alexander Gusev, Gosia Trynka, Yakir Reshef, Po Ru Loh, Verneri Anttila, Han Xu, Chongzhi Zang, Kyle Farh, Stephan Ripke, Felix R. Day, Shaun Purcell, Eli Stahl, Sara Lindstrom, John R.B. Perry, Yukinori Okada, Soumya Raychaudhuri, Mark J. Daly, Nick PattersonBenjamin M. Neale, Alkes L. Price

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1252 Scopus citations

Abstract

Recent work has demonstrated that some functional categories of the genome contribute disproportionately to the heritability of complex diseases. Here we analyze a broad set of functional elements, including cell type-specific elements, to estimate their polygenic contributions to heritability in genome-wide association studies (GWAS) of 17 complex diseases and traits with an average sample size of 73,599. To enable this analysis, we introduce a new method, stratified LD score regression, for partitioning heritability from GWAS summary statistics while accounting for linked markers. This new method is computationally tractable at very large sample sizes and leverages genome-wide information. Our findings include a large enrichment of heritability in conserved regions across many traits, a very large immunological disease-specific enrichment of heritability in FANTOM5 enhancers and many cell type-specific enrichments, including significant enrichment of central nervous system cell types in the heritability of body mass index, age at menarche, educational attainment and smoking behavior.

Original language	English (US)
Pages (from-to)	1228-1235
Number of pages	8
Journal	Nature Genetics
Volume	47
Issue number	11
DOIs	https://doi.org/10.1038/ng.3404
State	Published - Nov 1 2015
Externally published	Yes

ASJC Scopus subject areas

Genetics

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Finucane, H. K., Bulik-Sullivan, B., Gusev, A., Trynka, G., Reshef, Y., Loh, P. R., Anttila, V., Xu, H., Zang, C., Farh, K., Ripke, S., Day, F. R., Purcell, S., Stahl, E., Lindstrom, S., Perry, J. R. B., Okada, Y., Raychaudhuri, S., Daly, M. J., ... Price, A. L. (2015). Partitioning heritability by functional annotation using genome-wide association summary statistics. Nature Genetics, 47(11), 1228-1235. https://doi.org/10.1038/ng.3404

Finucane, HK, Bulik-Sullivan, B, Gusev, A, Trynka, G, Reshef, Y, Loh, PR, Anttila, V, Xu, H, Zang, C, Farh, K, Ripke, S, Day, FR, Purcell, S, Stahl, E, Lindstrom, S, Perry, JRB, Okada, Y, Raychaudhuri, S, Daly, MJ, Patterson, N, Neale, BM & Price, AL 2015, 'Partitioning heritability by functional annotation using genome-wide association summary statistics', Nature Genetics, vol. 47, no. 11, pp. 1228-1235. https://doi.org/10.1038/ng.3404

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abstract = "Recent work has demonstrated that some functional categories of the genome contribute disproportionately to the heritability of complex diseases. Here we analyze a broad set of functional elements, including cell type-specific elements, to estimate their polygenic contributions to heritability in genome-wide association studies (GWAS) of 17 complex diseases and traits with an average sample size of 73,599. To enable this analysis, we introduce a new method, stratified LD score regression, for partitioning heritability from GWAS summary statistics while accounting for linked markers. This new method is computationally tractable at very large sample sizes and leverages genome-wide information. Our findings include a large enrichment of heritability in conserved regions across many traits, a very large immunological disease-specific enrichment of heritability in FANTOM5 enhancers and many cell type-specific enrichments, including significant enrichment of central nervous system cell types in the heritability of body mass index, age at menarche, educational attainment and smoking behavior.",

author = "Finucane, {Hilary K.} and Brendan Bulik-Sullivan and Alexander Gusev and Gosia Trynka and Yakir Reshef and Loh, {Po Ru} and Verneri Anttila and Han Xu and Chongzhi Zang and Kyle Farh and Stephan Ripke and Day, {Felix R.} and Shaun Purcell and Eli Stahl and Sara Lindstrom and Perry, {John R.B.} and Yukinori Okada and Soumya Raychaudhuri and Daly, {Mark J.} and Nick Patterson and Neale, {Benjamin M.} and Price, {Alkes L.}",

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AU - Gusev, Alexander

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AU - Reshef, Yakir

AU - Loh, Po Ru

AU - Anttila, Verneri

AU - Xu, Han

AU - Zang, Chongzhi

AU - Farh, Kyle

AU - Ripke, Stephan

AU - Day, Felix R.

AU - Purcell, Shaun

AU - Stahl, Eli

AU - Lindstrom, Sara

AU - Perry, John R.B.

AU - Okada, Yukinori

AU - Raychaudhuri, Soumya

AU - Daly, Mark J.

AU - Patterson, Nick

AU - Neale, Benjamin M.

AU - Price, Alkes L.

PY - 2015/11/1

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

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