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 - Aslibekyan, Stella
AU - Becker, Diane
AU - Bi, Wenjian
AU - Brody, Jennifer
AU - Carlson, Jenna C.
AU - Correa, Adolfo
AU - Du, Margaret Mengmeng
AU - Fernandez-Rhodes, Lindsay
AU - Ferrier, Kendra R.
AU - Graff, Misa
AU - Guo, Xiuqing
AU - He, Jiang
AU - Heard-Costa, Nancy L.
AU - Highland, Heather M.
AU - Hirschhorn, Joel N.
AU - Howard-Claudio, Candace M.
AU - Isasi, Carmen R.
AU - Jackson, Rebecca
AU - Jiang, Jicai
AU - Joehanes, Roby
AU - Justice, Anne E.
AU - Kalyani, Rita R.
AU - Kardia, Sharon
AU - Lange, Ethan
AU - LeBoff, Meryl
AU - Lee, Seunggeun
AU - Li, Xihao
AU - Li, Zilin
AU - Lim, Elise
AU - Lin, Danyu
AU - Lin, Xihong
AU - Liu, Simin
AU - Arking, Dan
AU - Avramopoulos, Dimitrios
AU - Barron-Casella, Emily
AU - Beaty, Terri
AU - Becker, Lewis
AU - Casella, James
AU - Naik, Rakhi
AU - Post, Wendy
AU - Becker, Julia Powers
AU - Ruczinski, Ingo
AU - Salzberg, Steven
AU - Taub, Margaret
AU - Vaidya, Dhananjay
AU - Yanek, Lisa R.
AU - Mathias, Rasika A.
N1 - Funding Information:
P.M.V. was supported by the Australian Research Council (grant nos. DP160102400 and FL180100072), the Australian National Health and Medical Research Council (grant nos. 1113400 and 1078037) and the US National Institutes of Health (NIH; grant no. R01MH100141). J.Y. was supported by the Australian Research Council (grant no. FT180100186), the Sylvia & Charles Viertel Charitable Foundation and the Westlake Education Foundation. L.Y. was supported by the Australian Research Council (grant no. DE200100425). The present study makes use of data from the TOPMed program, the UKB and the UK10K projects. WGS for the TOPMed program was supported by the NHLBI. A full list of acknowledgements is provided in the Supplementary Information.
Funding Information:
P.M.V. was supported by the Australian Research Council (grant nos. DP160102400 and FL180100072), the Australian National Health and Medical Research Council (grant nos. 1113400 and 1078037) and the US National Institutes of Health (NIH; grant no. R01MH100141). J.Y. was supported by the Australian Research Council (grant no. FT180100186), the Sylvia & Charles Viertel Charitable Foundation and the Westlake Education Foundation. L.Y. was supported by the Australian Research Council (grant no. DE200100425). The present study makes use of data from the TOPMed program, the UKB and the UK10K projects. WGS for the TOPMed program was supported by the NHLBI. A full list of acknowledgements is provided in the .
Funding Information:
P.T.E. is supported by a grant from Bayer AG to the Broad Institute focused on the genetics and therapeutics of cardiovascular diseases. He has also served on advisory boards or consulted for Bayer AG, Quest Diagnostics and Novartis. S.A.L. receives sponsored research support from Bristol Myers Squibb/Pfizer, Bayer AG, Boehringer Ingelheim, Fitbit and IBM, and has consulted for Bristol Myers Squibb/Pfizer, Bayer AG and Blackstone Life Sciences. The other authors declare no competing interests.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2022/3
Y1 - 2022/3
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
SN - 1061-4036
VL - 54
SP - 263
EP - 273
JO - Nature genetics
JF - Nature genetics
IS - 3
ER -