Association of structural variation with cardiometabolic traits in Finns

Copyright © 2021. Published by Elsevier Inc..

The contribution of genome structural variation (SV) to quantitative traits associated with cardiometabolic diseases remains largely unknown. Here, we present the results of a study examining genetic association between SVs and cardiometabolic traits in the Finnish population. We used sensitive methods to identify and genotype 129,166 high-confidence SVs from deep whole-genome sequencing (WGS) data of 4,848 individuals. We tested the 64,572 common and low-frequency SVs for association with 116 quantitative traits and tested candidate associations using exome sequencing and array genotype data from an additional 15,205 individuals. We discovered 31 genome-wide significant associations at 15 loci, including 2 loci at which SVs have strong phenotypic effects: (1) a deletion of the ALB promoter that is greatly enriched in the Finnish population and causes decreased serum albumin level in carriers (p = 1.47 × 10-54) and is also associated with increased levels of total cholesterol (p = 1.22 × 10-28) and 14 additional cholesterol-related traits, and (2) a multi-allelic copy number variant (CNV) at PDPR that is strongly associated with pyruvate (p = 4.81 × 10-21) and alanine (p = 6.14 × 10-12) levels and resides within a structurally complex genomic region that has accumulated many rearrangements over evolutionary time. We also confirmed six previously reported associations, including five led by stronger signals in single nucleotide variants (SNVs) and one linking recurrent HP gene deletion and cholesterol levels (p = 6.24 × 10-10), which was also found to be strongly associated with increased glycoprotein level (p = 3.53 × 10-35). Our study confirms that integrating SVs in trait-mapping studies will expand our knowledge of genetic factors underlying disease risk.

Medienart:

E-Artikel

Erscheinungsjahr:

2021

Erschienen:

2021

Enthalten in:

Zur Gesamtaufnahme - volume:108

Enthalten in:

American journal of human genetics - 108(2021), 4 vom: 01. Apr., Seite 583-596

Sprache:

Englisch

Beteiligte Personen:

Chen, Lei [VerfasserIn]
Abel, Haley J [VerfasserIn]
Das, Indraniel [VerfasserIn]
Larson, David E [VerfasserIn]
Ganel, Liron [VerfasserIn]
Kanchi, Krishna L [VerfasserIn]
Regier, Allison A [VerfasserIn]
Young, Erica P [VerfasserIn]
Kang, Chul Joo [VerfasserIn]
Scott, Alexandra J [VerfasserIn]
Chiang, Colby [VerfasserIn]
Wang, Xinxin [VerfasserIn]
Lu, Shuangjia [VerfasserIn]
Christ, Ryan [VerfasserIn]
Service, Susan K [VerfasserIn]
Chiang, Charleston W K [VerfasserIn]
Havulinna, Aki S [VerfasserIn]
Kuusisto, Johanna [VerfasserIn]
Boehnke, Michael [VerfasserIn]
Laakso, Markku [VerfasserIn]
Palotie, Aarno [VerfasserIn]
Ripatti, Samuli [VerfasserIn]
Freimer, Nelson B [VerfasserIn]
Locke, Adam E [VerfasserIn]
Stitziel, Nathan O [VerfasserIn]
Hall, Ira M [VerfasserIn]

Links:

Volltext

Themen:

8558G7RUTR
97C5T2UQ7J
ALB protein, human
Cardiometabolic traits
Cholesterol
EC 3.1.3.43
Finnish population
Genome-wide association study
Journal Article
Mitochondrial Proteins
PDPR protein, human
Pyruvate Dehydrogenase (Lipoamide)-Phosphatase
Pyruvic Acid
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Serum Albumin, Human
Structural variation
ZIF514RVZR

Anmerkungen:

Date Completed 07.05.2021

Date Revised 11.01.2023

published: Print

Citation Status MEDLINE

doi:

10.1016/j.ajhg.2021.03.008

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM323539327