TY - JOUR
T1 - Genetic analysis in European ancestry individuals identifies 517 loci associated with liver enzymes
AU - LifeLines Cohort Study
AU - the 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 - Boezen, H. Marike
AU - Franke, Lude
AU - van der Harst, Pim
AU - Navis, Gerjan
AU - Rots, Marianne
AU - Swertz, Morris
AU - Wolffenbuttel, Bruce H.R.
AU - Wijmenga, Cisca
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 - Ballas, Zuhair K.
AU - Bhushan, Sujata
AU - Boyko, Edward J.
AU - Cohen, David M.
AU - Concato, John
AU - Aslan, Michaela
AU - Zhao, Hongyu
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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 - 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.
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U2 - 10.1038/s41467-021-22338-2
DO - 10.1038/s41467-021-22338-2
M3 - Article
C2 - 33972514
AN - SCOPUS:85105771079
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 2579
ER -