@article{8dd2c358c9324b71afaab46b92b31e5c,
title = "Allele-specific variation at APOE increases nonalcoholic fatty liver disease and obesity but decreases risk of Alzheimer's disease and myocardial infarction",
abstract = "Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease and is highly correlated with metabolic disease. NAFLD results from environmental exposures acting on a susceptible polygenic background. This study performed the largest multiethnic investigation of exonic variation associated with NAFLD and correlated metabolic traits and diseases. An exome array meta-analysis was carried out among eight multiethnic population-based cohorts (n=16 492) with computed tomography (CT) measured hepatic steatosis. A fixed effects meta-analysis identified five exome-wide significant loci (P<5.30×10-7); including a novel signal near TOMM40/APOE. Joint analysis of TOMM40/APOE variants revealed the TOMM40 signal was attributed to APOE rs429358-T; APOE rs7412 was not associated with liver attenuation. Moreover, rs429358-T was associated with higher serum alanine aminotransferase, liver steatosis, cirrhosis, triglycerides and obesity; as well as, lower cholesterol and decreased risk of myocardial infarction and Alzheimer{\textquoteright}s disease (AD) in phenome-wide association analyses in the Michigan Genomics Initiative, United Kingdom Biobank and/or public datasets. These results implicate APOE in imaging-based identification of NAFLD. This association may or may not translate to nonalcoholic steatohepatitis; however, these results indicate a significant association with advanced liver disease and hepatic cirrhosis. These findings highlight allelic heterogeneity at the APOE locus and demonstrate an inverse link between NAFLD and AD at the exome level in the largest analysis to date.",
author = "Palmer, {Nicholette D.} and Bratati Kahali and Annapurna Kuppa and Yanhua Chen and Xiaomeng Du and Feitosa, {Mary F.} and Bielak, {Lawrence F.} and O'Connell, {Jeffrey R.} and Musani, {Solomon K.} and Xiuqing Guo and Smith, {Albert V.} and Ryan, {Kathleen A.} and Gudny Eirksdottir and Allison, {Matthew A.} and Bowden, {Donald W.} and Budoff, {Matthew J.} and Carr, {J. Jeffrey} and Chen, {Yii Der I.} and Taylor, {Kent D.} and Adolfo Correa and Crudup, {Breland F.} and Brian Halligan and Jian Yang and Kardia, {Sharon L.R.} and Launer, {Lenore J.} and Fu, {Yi Ping} and Mosley, {Thomas H.} and Norris, {Jill M.} and Terry, {James G.} and O'Donnell, {Christopher J.} and Rotter, {Jerome I.} and Wagenknecht, {Lynne E.} and Vilmundur Gudnason and Province, {Michael A.} and Peyser, {Patricia A.} and Speliotes, {Elizabeth K.}",
note = "Funding Information: Age, Gene/Environment Susceptibility-Reykjavik Study (AGES) was funded by National Institutes of Health contract N01-AG-1-2100 and HHSN271201200022C, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee, VSN: 00-063. Genotyping was done at the Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas. Support for Family Heart Study (FamHS) was provided by the National Heart, Lung and Blood Institute (NHLBI) grant R01 HL08770003 and R01 HL117078 and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant R01 DK089256. The Framingham Heart Study is conducted and supported by the National Heart, Lung, and Blood Institute in collaboration with Boston University (Contract No. N01-HC-25195 and HHSN268201500001I). Funding for SHARe Affymetrix genotyping was provided by National Heart, Lung, and Blood Institute Contract N02-HL64278. SHARe Illumina genotyping was provided under an agreement between Illumina and Boston University. Funding for Affymetrix genotyping of the FHS Omni cohorts was provided by Intramural NHLBI funds from Andrew D. Johnson and Christopher J. O{\textquoteright}Donnell. Support for the Genetic Epidemiology Network of Arteriopathy (GENOA) study was provided by the National Institutes of Health, grant numbers HL085571, HL087660 and HL100245 from National Heart, Lung, and Blood Institute. Support for the Insulin Resistance Atherosclerosis Family Study (IRASFS) was provided by the National Heart, Lung, and Blood Institute grants R01 HL060944, R01 HL061019, R01 HL060919, R01 HL060894 and R01 HL061210 and NIDDK grant DK085175 and DK118062. IRASFS genotyping was carried out with funds from the Department of Internal Medicine at the University of Michigan. Analysis was partially supported by the Mid-Atlantic Nutrition Obesity Research Center (P30 DK072488) from the NIDDK. The Jackson Heart Study (JHS) is supported and conducted in collaboration with Jackson State University (HHSN268201800013I), Tougaloo College (HHSN268201800014I), the Mississippi State Department of Health (HHSN268201800015I) and the University of Mississippi Medical Center (HHSN268201800010I, HHSN268201800011I and HHSN268201800012I) contracts from the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute on Minority Health and Health Disparities (NIMHD). The authors also wish to thank the staffs and participants of the JHS. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services. MESA and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420. Liver phenotyping is MESA was made possible by R01 HL088451. MESA is also supported, in part, by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the NIDDK Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The Old Order Amish (OOA) studies are supported by grants and contracts from National Institutes of Health, including U01 HL072515, U01 HL84756, U01 HL137181 and P30 DK72488. The authors acknowledge the Michigan Genomics Initiative participants, Precision Health at the University of Michigan, the University of Michigan Medical School Central Biorepository, and the University of Michigan Advanced Genomics Core for providing data and specimen storage, management, processing, and distribution services, and the Center for Statistical Genetics in the Department of Biostatistics at the School of Public Health for genotype data curation, imputation, and management in support of the research reported in this publication. Analyses in the UKBB were done under approved project 18120 (EKS). The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. This manuscript was not prepared in collaboration with investigators of the WHI, has not been reviewed and/or approved by the Women{\textquoteright}{\textquoteright}s Health Initiative (WHI), and does not necessarily reflect the opinions of the WHI investigators or the NHLBI. This study makes use of data from dbGaP HRS (dbGaP accession: phs000428.v1.p1): HRS is supported by the National Institute on Aging (NIA U01AG009740). The genotyping was funded separately by the National Institute on Aging (RC2 AG036495, RC4 AG039029). Genotyping was conducted by the NIH Center for Inherited Disease Research (CIDR) at Johns Hopkins University. Genotyping quality control and final preparation of the data were performed by the Genetics Coordinating Center at the University of Washington. In addition, we would like to acknowledge the American Diabetes Association Mentor-Based Postdoctoral Fellowship Program (7-07-MN-08, RH). National Institutes of Health (grants R01 DK106621 to EKS, BK, YC, AK, XD and BH; RO1 DK107904 to EKS) and The University of Michigan Department of Internal Medicine. Publisher Copyright: {\textcopyright} The Author(s) 2021. Published by Oxford University Press. All rights reserved.",
year = "2021",
month = aug,
day = "1",
doi = "10.1093/hmg/ddab096",
language = "English",
volume = "30",
pages = "1443--1456",
journal = "Human molecular genetics",
issn = "0964-6906",
number = "15",
}