Skip to main content

Assessing the contribution of rare variants to complex trait heritability from whole-genome sequence data.

Publication ,  Journal Article
Wainschtein, P; Jain, D; Zheng, Z; TOPMed Anthropometry Working Group, ; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, ; Cupples, LA ...
Published in: Nat Genet
March 2022

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.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Nat Genet

DOI

EISSN

1546-1718

Publication Date

March 2022

Volume

54

Issue

3

Start / End Page

263 / 273

Location

United States

Related Subject Headings

  • Polymorphism, Single Nucleotide
  • Multifactorial Inheritance
  • Linkage Disequilibrium
  • Humans
  • Genome-Wide Association Study
  • Developmental Biology
  • Alleles
  • 3105 Genetics
  • 3102 Bioinformatics and computational biology
  • 3001 Agricultural biotechnology
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Wainschtein, P., Jain, D., Zheng, Z., TOPMed Anthropometry Working Group, ., NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, ., Cupples, L. A., … Visscher, P. M. (2022). Assessing the contribution of rare variants to complex trait heritability from whole-genome sequence data. Nat Genet, 54(3), 263–273. https://doi.org/10.1038/s41588-021-00997-7
Wainschtein, Pierrick, Deepti Jain, Zhili Zheng, Zhili TOPMed Anthropometry Working Group, Zhili NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, L Adrienne Cupples, Aladdin H. Shadyab, et al. “Assessing the contribution of rare variants to complex trait heritability from whole-genome sequence data.Nat Genet 54, no. 3 (March 2022): 263–73. https://doi.org/10.1038/s41588-021-00997-7.
Wainschtein P, Jain D, Zheng Z, TOPMed Anthropometry Working Group, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Cupples LA, et al. Assessing the contribution of rare variants to complex trait heritability from whole-genome sequence data. Nat Genet. 2022 Mar;54(3):263–73.
Wainschtein, Pierrick, et al. “Assessing the contribution of rare variants to complex trait heritability from whole-genome sequence data.Nat Genet, vol. 54, no. 3, Mar. 2022, pp. 263–73. Pubmed, doi:10.1038/s41588-021-00997-7.
Wainschtein P, Jain D, Zheng Z, TOPMed Anthropometry Working Group, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Cupples LA, Shadyab AH, McKnight B, Shoemaker BM, Mitchell BD, Psaty BM, Kooperberg C, Liu C-T, Albert CM, Roden D, Chasman DI, Darbar D, Lloyd-Jones DM, Arnett DK, Regan EA, Boerwinkle E, Rotter JI, O’Connell JR, Yanek LR, de Andrade M, Allison MA, McDonald M-LN, Chung MK, Fornage M, Chami N, Smith NL, Ellinor PT, Vasan RS, Mathias RA, Loos RJF, Rich SS, Lubitz SA, Heckbert SR, Redline S, Guo X, Chen Y-DI, Laurie CA, Hernandez RD, McGarvey ST, Goddard ME, Laurie CC, North KE, Lange LA, Weir BS, Yengo L, Yang J, Visscher PM. Assessing the contribution of rare variants to complex trait heritability from whole-genome sequence data. Nat Genet. 2022 Mar;54(3):263–273.

Published In

Nat Genet

DOI

EISSN

1546-1718

Publication Date

March 2022

Volume

54

Issue

3

Start / End Page

263 / 273

Location

United States

Related Subject Headings

  • Polymorphism, Single Nucleotide
  • Multifactorial Inheritance
  • Linkage Disequilibrium
  • Humans
  • Genome-Wide Association Study
  • Developmental Biology
  • Alleles
  • 3105 Genetics
  • 3102 Bioinformatics and computational biology
  • 3001 Agricultural biotechnology