TY - JOUR
T1 - Assessing the contribution of rare variants to complex trait heritability from whole-genome sequence data
AU - TOPMed Anthropometry Working Group
AU - NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
AU - Wainschtein, Pierrick
AU - Jain, Deepti
AU - Zheng, Zhili
AU - Cupples, L. Adrienne
AU - Shadyab, Aladdin H.
AU - McKnight, Barbara
AU - Shoemaker, Benjamin M.
AU - Mitchell, Braxton D.
AU - Psaty, Bruce M.
AU - Kooperberg, Charles
AU - Liu, Ching Ti
AU - Albert, Christine M.
AU - Roden, Dan
AU - Chasman, Daniel I.
AU - Darbar, Dawood
AU - Lloyd-Jones, Donald M.
AU - Arnett, Donna K.
AU - Regan, Elizabeth A.
AU - Boerwinkle, Eric
AU - Rotter, Jerome I.
AU - O'Connell, Jeffrey R.
AU - Yanek, Lisa R.
AU - de Andrade, Mariza
AU - Allison, Matthew A.
AU - McDonald, Merry Lynn N.
AU - Chung, Mina K.
AU - Fornage, Myriam
AU - Chami, Nathalie
AU - Smith, Nicholas L.
AU - Ellinor, Patrick T.
AU - Vasan, Ramachandran S.
AU - Mathias, Rasika A.
AU - Loos, Ruth J.F.
AU - Rich, Stephen S.
AU - Lubitz, Steven A.
AU - Heckbert, Susan R.
AU - Redline, Susan
AU - Guo, Xiuqing
AU - Chen, Y. D.Ida
AU - Laurie, Cecelia A.
AU - Hernandez, Ryan D.
AU - McGarvey, Stephen T.
AU - Goddard, Michael E.
AU - Laurie, Cathy C.
AU - North, Kari E.
AU - Lange, Leslie A.
AU - Weir, Bruce S.
AU - Yengo, Loic
AU - Yang, Jian
AU - Visscher, Peter M.
N1 - Publisher Copyright:
© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2022/3/1
Y1 - 2022/3/1
N2 - Analyses of data from genome-wide association studies on unrelated individuals have shown that, for human traits and diseases, approximately one-third to two-thirds of heritability is captured by common SNPs. However, it is not known whether the remaining heritability is due to the imperfect tagging of causal variants by common SNPs, in particular whether the causal variants are rare, or whether it is overestimated due to bias in inference from pedigree data. Here we estimated heritability for height and body mass index (BMI) from whole-genome sequence data on 25,465 unrelated individuals of European ancestry. The estimated heritability was 0.68 (standard error 0.10) for height and 0.30 (standard error 0.10) for body mass index. Low minor allele frequency variants in low linkage disequilibrium (LD) with neighboring variants were enriched for heritability, to a greater extent for protein-altering variants, consistent with negative selection. Our results imply that rare variants, in particular those in regions of low linkage disequilibrium, are a major source of the still missing heritability of complex traits and disease.
AB - Analyses of data from genome-wide association studies on unrelated individuals have shown that, for human traits and diseases, approximately one-third to two-thirds of heritability is captured by common SNPs. However, it is not known whether the remaining heritability is due to the imperfect tagging of causal variants by common SNPs, in particular whether the causal variants are rare, or whether it is overestimated due to bias in inference from pedigree data. Here we estimated heritability for height and body mass index (BMI) from whole-genome sequence data on 25,465 unrelated individuals of European ancestry. The estimated heritability was 0.68 (standard error 0.10) for height and 0.30 (standard error 0.10) for body mass index. Low minor allele frequency variants in low linkage disequilibrium (LD) with neighboring variants were enriched for heritability, to a greater extent for protein-altering variants, consistent with negative selection. Our results imply that rare variants, in particular those in regions of low linkage disequilibrium, are a major source of the still missing heritability of complex traits and disease.
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U2 - 10.1038/s41588-021-00997-7
DO - 10.1038/s41588-021-00997-7
M3 - Article
C2 - 35256806
AN - SCOPUS:85126125467
VL - 54
SP - 263
EP - 273
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 3
ER -