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; ReproGen Consortium; Schizophrenia Working Group of the Psychiatric Genomics Consortium; The RACI Consortium; 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
, ReproGen Consortium
, Schizophrenia Working Group of the Psychiatric Genomics Consortium
, The RACI Consortium
, 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^*

^*Corresponding author for this work

Broad Institute of MIT and Harvard
Massachusetts General Hospital and Harvard Medical School
Harvard T.H. Chan School of Public Health
Harvard Pilgrim Health Care Institute
Harvard University
Dana-Farber Cancer Institute
Icahn School of Medicine at Mount Sinai
Tokyo Medical and Dental University
University of Cambridge School of Clinical Medicine

Research output: Contribution to journal › Article › Academic › peer-review

1774 Citations (Scopus)

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
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
Publication status	Published - Nov 2015

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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., ReproGen Consortium, Schizophrenia Working Group of the Psychiatric Genomics Consortium, The RACI Consortium, Purcell, S., Stahl, E., Lindstrom, S., Perry, J. R. B., ... 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

@article{c76022d49bfb4d37acef7067d9370d5a,

title = "Partitioning heritability by functional annotation using genome-wide association summary statistics",

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 Po-Ru Loh and Verneri Anttila and Han Xu and Chongzhi Zang and Kyle Farh and Stephan Ripke and Day, \{Felix R\} and \{ReproGen Consortium\} and \{Schizophrenia Working Group of the Psychiatric Genomics Consortium\} and \{The RACI Consortium\} 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\} and Lisette Stolk and Visser, \{Jenny A.\} and Andr{\'e} Uitterlinden and Fernando Rivadeneira and \{van Meurs\}, Joyce and Bert Hofman and Joop Laven",

year = "2015",

month = nov,

doi = "10.1038/ng.3404",

language = "English",

volume = "47",

pages = "1228--1235",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "11",

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Finucane, HK, Bulik-Sullivan, B, Gusev, A, Trynka, G, Reshef, Y, Loh, P-R, Anttila, V, Xu, H, Zang, C, Farh, K, Ripke, S, Day, FR, ReproGen Consortium, Schizophrenia Working Group of the Psychiatric Genomics Consortium, The RACI Consortium, 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

TY - JOUR

T1 - Partitioning heritability by functional annotation using genome-wide association summary statistics

AU - Finucane, Hilary K

AU - Bulik-Sullivan, Brendan

AU - Gusev, Alexander

AU - Trynka, Gosia

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 - ReproGen Consortium

AU - Schizophrenia Working Group of the Psychiatric Genomics Consortium

AU - The RACI Consortium

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

AU - Stolk, Lisette

AU - Visser, Jenny A.

AU - Uitterlinden, André

AU - Rivadeneira, Fernando

AU - van Meurs, Joyce

AU - Hofman, Bert

AU - Laven, Joop

PY - 2015/11

Y1 - 2015/11

N2 - 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.

AB - 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.

U2 - 10.1038/ng.3404

DO - 10.1038/ng.3404

M3 - Article

C2 - 26414678

SN - 1061-4036

VL - 47

SP - 1228

EP - 1235

JO - Nature Genetics

JF - Nature Genetics

IS - 11

ER -

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

Abstract

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