Identification of 90 NAFLD GWAS loci and establishment of NAFLD PRS and causal role of NAFLD in coronary artery disease

Zong Miao; Kristina M. Garske; David Z. Pan; Amogha Koka; Dorota Kaminska; Ville Männistö; Janet S. Sinsheimer; Jussi Pihlajamäki; Päivi Pajukanta

HGG Advances (Jan 2022)

Identification of 90 NAFLD GWAS loci and establishment of NAFLD PRS and causal role of NAFLD in coronary artery disease

Zong Miao,
Kristina M. Garske,
David Z. Pan,
Amogha Koka,
Dorota Kaminska,
Ville Männistö,
Janet S. Sinsheimer,
Jussi Pihlajamäki,
Päivi Pajukanta

Affiliations

Zong Miao: Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Bioinformatics Interdepartmental Program, UCLA, Los Angeles, CA, USA
Kristina M. Garske: Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
David Z. Pan: Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Bioinformatics Interdepartmental Program, UCLA, Los Angeles, CA, USA
Amogha Koka: Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
Dorota Kaminska: Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Institute of Public Health and Clinical Nutrition UEF, Kuopio, Finland; Turku PET Centre, Turku University Hospital, Turku, Finland
Ville Männistö: Department of Medicine, UEF and Kuopio University Hospital, Kuopio, Finland; Department of Experimental Vascular Medicine, Amsterdam UMC, Location AMC at University of Amsterdam, Amsterdam, the Netherlands
Janet S. Sinsheimer: Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Bioinformatics Interdepartmental Program, UCLA, Los Angeles, CA, USA; Department of Computational Medicine, UCLA, Los Angeles, CA, USA
Jussi Pihlajamäki: Institute of Public Health and Clinical Nutrition UEF, Kuopio, Finland; Department of Medicine, Endocrinology, and Clinical Nutrition, Kuopio University Hospital, Kuopio, Finland
Päivi Pajukanta: Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Bioinformatics Interdepartmental Program, UCLA, Los Angeles, CA, USA; Institute for Precision Health, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Corresponding author

Journal volume & issue: Vol. 3, no. 1
p. 100056

Abstract

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Summary: The prevalence of non-alcoholic fatty liver disease (NAFLD), now also known as metabolic dysfunction-associated fatty liver disease (MAFLD), is rapidly increasing worldwide due to the ongoing obesity epidemic. However, currently the NALFD diagnosis requires non-readily available imaging technologies or liver biopsy, which has drastically limited the sample sizes of NAFLD studies and hampered the discovery of its genetic component. Here we utilized the large UK Biobank (UKB) to accurately estimate the NAFLD status in UKB based on common serum traits and anthropometric measures. Scoring all individuals in UKB for NAFLD risk resulted in 28,396 NAFLD cases and 108,652 healthy individuals at a >90% confidence level. Using this imputed NAFLD status to perform the largest NAFLD genome-wide association study (GWAS) to date, we identified 94 independent (R2 < 0.2) NAFLD GWAS loci, of which 90 have not been identified before; built a polygenic risk score (PRS) model to predict the genetic risk of NAFLD; and used the GWAS variants of imputed NAFLD for a tissue-aware Mendelian randomization analysis that discovered a significant causal effect of NAFLD on coronary artery disease (CAD). In summary, we accurately estimated the NAFLD status in UKB using common serum traits and anthropometric measures, which empowered us to identify 90 GWAS NAFLD loci, build NAFLD PRS, and discover a significant causal effect of NAFLD on CAD.

Published in HGG Advances

ISSN: 2666-2477 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science: Biology (General): Genetics
Website: https://www.cell.com/hgg-advances/home

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