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

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AMP-T2D-GENES, Myocardial Infarction Genetics Consortium. / Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes. I: American Journal of Human Genetics. 2022 ; Bind 109, Nr. 1. s. 81-96.

Bibtex

@article{9c277d4f385c4ab7b53cd5b1547ce0e8,
title = "Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes",
abstract = "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.",
author = "George Hindy and Peter Dornbos and Chaffin, {Mark D} and Liu, {Dajiang J} and Minxian Wang and Selvaraj, {Margaret Sunitha} and David Zhang and Joseph Park and Aguilar-Salinas, {Carlos A} and Lucinda Antonacci-Fulton and Diego Ardissino and Arnett, {Donna K} and Stella Aslibekyan and Gil Atzmon and Ballantyne, {Christie M} and Francisco Barajas-Olmos and Nir Barzilai and Becker, {Lewis C} and Bielak, {Lawrence F} and Bis, {Joshua C} and John Blangero and Eric Boerwinkle and Bonnycastle, {Lori L} and Erwin Bottinger and Bowden, {Donald W} and Bown, {Matthew J} and Brody, {Jennifer A} and Broome, {Jai G} and Burtt, {No{\"e}l P} and Cade, {Brian E} and Federico Centeno-Cruz and Edmund Chan and Yi-Cheng Chang and Chen, {Yii-Der I} and Ching-Yu Cheng and Choi, {Won Jung} and Rajiv Chowdhury and Cecilia Contreras-Cubas and C{\'o}rdova, {Emilio J} and Adolfo Correa and Cupples, {L Adrienne} and Curran, {Joanne E} and John Danesh and {de Vries}, {Paul S} and DeFronzo, {Ralph A} and Harsha Doddapaneni and Ravindranath Duggirala and Dutcher, {Susan K} and Torben Hansen and Allan Linneberg and {AMP-T2D-GENES, Myocardial Infarction Genetics Consortium}",
note = "Copyright {\textcopyright} 2021 American Society of Human Genetics. All rights reserved.",
year = "2022",
month = jan,
day = "6",
doi = "10.1016/j.ajhg.2021.11.021",
language = "English",
volume = "109",
pages = "81--96",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "1",

}

RIS

TY - JOUR

T1 - Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes

AU - Hindy, George

AU - Dornbos, Peter

AU - Chaffin, Mark D

AU - Liu, Dajiang J

AU - Wang, Minxian

AU - Selvaraj, Margaret Sunitha

AU - Zhang, David

AU - Park, Joseph

AU - Aguilar-Salinas, Carlos A

AU - Antonacci-Fulton, Lucinda

AU - Ardissino, Diego

AU - Arnett, Donna K

AU - Aslibekyan, Stella

AU - Atzmon, Gil

AU - Ballantyne, Christie M

AU - Barajas-Olmos, Francisco

AU - Barzilai, Nir

AU - Becker, Lewis C

AU - Bielak, Lawrence F

AU - Bis, Joshua C

AU - Blangero, John

AU - Boerwinkle, Eric

AU - Bonnycastle, Lori L

AU - Bottinger, Erwin

AU - Bowden, Donald W

AU - Bown, Matthew J

AU - Brody, Jennifer A

AU - Broome, Jai G

AU - Burtt, Noël P

AU - Cade, Brian E

AU - Centeno-Cruz, Federico

AU - Chan, Edmund

AU - Chang, Yi-Cheng

AU - Chen, Yii-Der I

AU - Cheng, Ching-Yu

AU - Choi, Won Jung

AU - Chowdhury, Rajiv

AU - Contreras-Cubas, Cecilia

AU - Córdova, Emilio J

AU - Correa, Adolfo

AU - Cupples, L Adrienne

AU - Curran, Joanne E

AU - Danesh, John

AU - de Vries, Paul S

AU - DeFronzo, Ralph A

AU - Doddapaneni, Harsha

AU - Duggirala, Ravindranath

AU - Dutcher, Susan K

AU - Hansen, Torben

AU - Linneberg, Allan

AU - AMP-T2D-GENES, Myocardial Infarction Genetics Consortium

N1 - Copyright © 2021 American Society of Human Genetics. All rights reserved.

PY - 2022/1/6

Y1 - 2022/1/6

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85122004213&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2021.11.021

DO - 10.1016/j.ajhg.2021.11.021

M3 - Journal article

C2 - 34932938

VL - 109

SP - 81

EP - 96

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 1

ER -

ID: 70538169