Rare coding variants in 35 genes associate with circulating lipid levels—A multi-ancestry analysis of 170,000 exomes

• Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency < 1%) predicted damaging coding variation by using sequence data from >170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels; some of these genes have not been previously associated with lipid levels when using rare coding variation from population-based samples. We prioritize 32 genes in array-based genome-wide association study (GWAS) loci based on aggregations of rare coding variants; three (EVI5, SH2B3, and PLIN1) had no prior association of rare coding variants with lipid levels. Most of our associated genes showed evidence of association among multiple ancestries. Finally, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes and for genes closest to GWAS index single-nucleotide polymorphisms (SNPs). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels. © 2021 American Society of Human Genetics

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Medical Genetics (hsv//eng)

Nyckelord

association

cholesterol

exome sequencing

gene-based association

lipid

high density lipoprotein cholesterol

low density lipoprotein cholesterol

triacylglycerol

African

ALB gene

ancestry group

Article

cholesterol blood level

CREB3L3 gene

East Asian

European

exosome

gene

gene frequency

gene identification

gene sequence

genetic association

genetic code

genetic trait

genetic variability

genome-wide association study

high density lipoprotein cholesterol level

Hispanic

human

JAK2 gene

lipid blood level

lipid level

lipid metabolism

low density lipoprotein cholesterol level

molecular genetics

NR1H3 gene

PLA2G12A gene

population genetics

PPARG gene

Samoan (people)

single nucleotide polymorphism

South Asian

SRSF2 gene

STAB1 gene

TMEM136 gene

triacylglycerol blood level

VARS gene

whole exome sequencing

allele

biology

blood

case control study

exome

genetic database

genetic predisposition

genetic variation

genetics

glucose blood level

liver

metabolism

multifactorial inheritance

non insulin dependent diabetes mellitus

open reading frame

pathology

phenotype

procedures

Alleles

Blood Glucose

Case-Control Studies

Computational Biology

Databases, Genetic

Diabetes Mellitus, Type 2

Exome

Genetic Predisposition to Disease

Genetic Variation

Genetics, Population

Genome-Wide Association Study

Humans

Lipid Metabolism

Lipids

Liver

Molecular Sequence Annotation

Multifactorial Inheritance

Open Reading Frames

Phenotype

Polymorphism, Single Nucleotide

Publikations- och innehållstyp

art (ämneskategori)

ref (ämneskategori)