HUNT custom genotyping and TOPMed imputation GWAS summary statistics for lipid and liver-related blood traits

Result Files

HUNT GWAS summary statistics based on TOPMed imputation (9 files)

Trans-ancestry GWAS summary statistics based meta-analyses of HUNT, SardiNIA, and Biobank Japan (9 files)

Reference

Nielsen, Rom et al. (2021) Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease.
Nature Communications 2020 Dec 18;11(1):6417. doi: 10.1038/s41467-020-20086-3. [online at Nature] [online at PubMed]

Description

For 69,479 participants in the HUNT Study, we imputed from the TOPMed imputation reference panel 26 million genomic variants with sufficient quality and at least 10 minor allele copies. Using a linear mixed model to account for relatedness among study participants, we tested for genome-wide association (P < 5e-8) with 9 blood traits related to lipids (HDL-C, LDL-C, TG, TC), liver health (ALT, ALP, AST, GGT), or inflammation (CRP). We identified 201 genomic regions (i.e., loci) associated with one or more of the traits. At 24 of the 201 loci, the locus index variant alters (n=22) or results in loss-of-function (LoF) (n=2) of the protein. Stepwise conditional analyses resulted in identification of additional 150 independently associated variants within the 201 loci. These include 28 additional protein-altering variants, hereof 2 LoF variants, which are significantly and independently associated with one or more of the liver-related blood traits. For the purpose of further fine-mapping of loci and identification of additional presumed causal protein-altering variants, we performed trans-ancestry meta-analyses by combining summary statistics based on the primary discovery effort in HUNT with additional GWAS statistics from Sardinia (SardiNIA cohort) and Japan (Biobank Japan). The combined meta-analyses comprised up to 203,476 participants (N range 128,794 for CRP to 203,476 for TC) and 31.5 million unique variants (n range 24.7–31.5 million) (Supplementary Fig. 3). The analyses and resulted in identification of an additional 86 loci and 351 independent variants, including 13 presumed causal protein-altering variants. Lastly, we conducted custom content genotyping of rare HUNT region-specific protein-altering variants and identified 11 protein-altering variants, including 4 LoF variants associated with one or more of the 9 blood traits.

Please e-mail Goncalo Abecasis or Cristen Willer with comments or suggestions.