TY - JOUR
T1 - Genetic analysis in European ancestry individuals identifies 517 loci associated with liver enzymes
AU - Lifelines Cohort Study
AU - VA Million Veteran Program
AU - Pazoki, Raha
AU - Vujkovic, Marijana
AU - Elliott, Joshua
AU - Evangelou, Evangelos
AU - Gill, Dipender
AU - Ghanbari, Mohsen
AU - van der Most, Peter J.
AU - Pinto, Rui Climaco
AU - Wielscher, Matthias
AU - Farlik, Matthias
AU - Zuber, Verena
AU - de Knegt, Robert J.
AU - Snieder, Harold
AU - Uitterlinden, André G.
AU - Lynch, Julie A.
AU - Jiang, Xiyun
AU - Said, Saredo
AU - Kaplan, David E.
AU - Lee, Kyung Min
AU - Serper, Marina
AU - Carr, Rotonya M.
AU - Tsao, Philip S.
AU - Atkinson, Stephen R.
AU - Dehghan, Abbas
AU - Tzoulaki, Ioanna
AU - Ikram, M. Arfan
AU - Herzig, Karl Heinz
AU - Järvelin, Marjo Riitta
AU - Alizadeh, Behrooz Z.
AU - O'Donnell, Christopher J.
AU - Saleheen, Danish
AU - Voight, Benjamin F.
AU - Chang, Kyong Mi
AU - Thursz, Mark R.
AU - Elliott, Paul
AU - Rots, Marianne
N1 - Copyright:
This record is sourced from MEDLINE/PubMed, a database of the U.S. National Library of Medicine
PY - 2021/5/10
Y1 - 2021/5/10
N2 - Plasma levels of liver enzymes provide insights into hepatic function and related diseases. Here, the authors perform a genome-wide association study on three liver enzymes, identifying genetic variants associated with their plasma concentration as well as links to metabolic and cardiovascular diseases.Serum concentration of hepatic enzymes are linked to liver dysfunction, metabolic and cardiovascular diseases. We perform genetic analysis on serum levels of alanine transaminase (ALT), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) using data on 437,438 UK Biobank participants. Replication in 315,572 individuals from European descent from the Million Veteran Program, Rotterdam Study and Lifeline study confirms 517 liver enzyme SNPs. Genetic risk score analysis using the identified SNPs is strongly associated with serum activity of liver enzymes in two independent European descent studies (The Airwave Health Monitoring study and the Northern Finland Birth Cohort 1966). Gene-set enrichment analysis using the identified SNPs highlights involvement in liver development and function, lipid metabolism, insulin resistance, and vascular formation. Mendelian randomization analysis shows association of liver enzyme variants with coronary heart disease and ischemic stroke. Genetic risk score for elevated serum activity of liver enzymes is associated with higher fat percentage of body, trunk, and liver and body mass index. Our study highlights the role of molecular pathways regulated by the liver in metabolic disorders and cardiovascular disease.
AB - Plasma levels of liver enzymes provide insights into hepatic function and related diseases. Here, the authors perform a genome-wide association study on three liver enzymes, identifying genetic variants associated with their plasma concentration as well as links to metabolic and cardiovascular diseases.Serum concentration of hepatic enzymes are linked to liver dysfunction, metabolic and cardiovascular diseases. We perform genetic analysis on serum levels of alanine transaminase (ALT), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) using data on 437,438 UK Biobank participants. Replication in 315,572 individuals from European descent from the Million Veteran Program, Rotterdam Study and Lifeline study confirms 517 liver enzyme SNPs. Genetic risk score analysis using the identified SNPs is strongly associated with serum activity of liver enzymes in two independent European descent studies (The Airwave Health Monitoring study and the Northern Finland Birth Cohort 1966). Gene-set enrichment analysis using the identified SNPs highlights involvement in liver development and function, lipid metabolism, insulin resistance, and vascular formation. Mendelian randomization analysis shows association of liver enzyme variants with coronary heart disease and ischemic stroke. Genetic risk score for elevated serum activity of liver enzymes is associated with higher fat percentage of body, trunk, and liver and body mass index. Our study highlights the role of molecular pathways regulated by the liver in metabolic disorders and cardiovascular disease.
KW - GENOME-WIDE ASSOCIATION
KW - LD SCORE REGRESSION
KW - MENDELIAN RANDOMIZATION
KW - DISEASE
KW - METAANALYSIS
KW - BIOBANK
KW - RISK
KW - HERITABILITY
KW - POPULATION
KW - HEALTH
UR - http://www.scopus.com/inward/record.url?scp=85105771079&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-22338-2
DO - 10.1038/s41467-021-22338-2
M3 - Article
C2 - 33972514
SN - 2041-1723
VL - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 2579
ER -