GWAS and enrichment analyses of non-alcoholic fatty liver disease identify new trait-associated genes and pathways across eMERGE Network

被引：122

作者：

Namjou, Bahram ^{[1
,2
]}

Lingren, Todd ^{[2
,3
]}

Huang, Yongbo ^{[1
]}

Parameswaran, Sreeja ^{[1
]}

Cobb, Beth L. ^{[1
]}

Stanaway, Ian B. ^{[4
]}

Connolly, John J. ^{[5
]}

Mentch, Frank D. ^{[5
]}

Benoit, Barbara ^{[6
]}

Niu, Xinnan ^{[7
,8
]}

Wei, Wei-Qi ^{[7
,8
]}

Carroll, Robert J. ^{[7
,8
]}

Pacheco, Jennifer A. ^{[9
]}

Harley, Isaac T. W. ^{[10
,11
]}

Divanovic, Senad ^{[10
,11
]}

Carrell, David S. ^{[12
]}

Larson, Eric B. ^{[12
]}

Carey, David J. ^{[13
]}

Verma, Shefali ^{[14
]}

Ritchie, Marylyn D. ^{[14
]}

Gharavi, Ali G. ^{[15
]}

Murphy, Shawn ^{[16
]}

Williams, Marc S. ^{[17
]}

Crosslin, David R. ^{[4
]}

Jarvik, Gail P. ^{[18
,19
]}

Kullo, Iftikhar J. ^{[20
]}

Hakonarson, Hakon ^{[5
,21
]}

Li, Rongling ^{[22
]}

Xanthakos, Stavra A. ^{[23
]}

Harley, John B. ^{[1
,2
,24
]}

机构：

[1] Cincinnati Childrens Hosp Med Ctr, Ctr Autoimmune Genom & Etiol, Cincinnati, OH 45229 USA

[2] Univ Cincinnati, Coll Med, 3333 Burnet Ave, Cincinnati, OH 45229 USA

[3] Cincinnati Childrens Hosp Med Ctr, Div Biomed Informat, Cincinnati, OH 45229 USA

[4] Univ Washington, Sch Med, Dept Biomed Informat Med Educ, Seattle, WA USA

[5] Childrens Hosp Philadelphia, Ctr Appl Genom, Bethesda, MD USA

[6] Harvard Univ, Partners HealthCare, Res IS & Comp, Somerville, MA USA

[7] Vanderbilt Univ, Dept Biomed Informat, 221 Kirkland Hall, Nashville, TN 37235 USA

[8] Vanderbilt Univ, Dept Med, Nashville, TN USA

[9] Northwestern Univ, Feinberg Sch Med, Ctr Genet Med, Chicago, IL 60611 USA

[10] Cincinnati Childrens Hosp Res Fdn, Dept Pediat, Div Immunol, Cincinnati, OH USA

[11] Univ Cincinnati, Coll Med, Cincinnati, OH USA

[12] Kaiser Permanente, Kaiser Permanente Washington Hlth Res Inst, Seattle, WA USA

[13] Geisinger, Dept Mol & Funct Gen, Danville, PA USA

[14] Univ Penn, Dept Genet, Philadelphia, PA 19104 USA

[15] Columbia Univ, Dept Med, New York, NY USA

[16] Partners HealthCare, Res Informat Sci & Comp, Boston, MA USA

[17] Geisinger, Genom Med Inst, Danville, PA USA

[18] Univ Washington, Med Ctr, Dept Med Med Genet, Seattle, WA 98195 USA

[19] Univ Washington, Med Ctr, Dept Genome Sci, Seattle, WA 98195 USA

[20] Mayo Clin, Dept Cardiovasc Dis, Rochester, MN USA

[21] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA

[22] NHGRI, NIH, Bethesda, MD 20892 USA

[23] Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Sch Med, Dept Pediat,Div Gastroenterol Hepatol & Nutr, Cincinnati, OH USA

[24] US Dept Vet Affairs, Med Ctr, Cincinnati, OH USA

来源：

BMC MEDICINE | 2019年 / 17卷 / 1期

关键词：

NAFLD; Fatty liver; Genetic polymorphism; GWAS; PheWAS; Polygenic risk score; GENOME-WIDE ASSOCIATION; URIC-ACID; PROGRESSION; EXPRESSION; VARIANTS; PNPLA3; SCAN; POLYMORPHISMS; VALIDATION; STEATOSIS;

D O I：

10.1186/s12916-019-1364-z

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

BackgroundNon-alcoholic fatty liver disease (NAFLD) is a common chronic liver illness with a genetically heterogeneous background that can be accompanied by considerable morbidity and attendant health care costs. The pathogenesis and progression of NAFLD is complex with many unanswered questions. We conducted genome-wide association studies (GWASs) using both adult and pediatric participants from the Electronic Medical Records and Genomics (eMERGE) Network to identify novel genetic contributors to this condition.MethodsFirst, a natural language processing (NLP) algorithm was developed, tested, and deployed at each site to identify 1106 NAFLD cases and 8571 controls and histological data from liver tissue in 235 available participants. These include 1242 pediatric participants (396 cases, 846 controls). The algorithm included billing codes, text queries, laboratory values, and medication records. Next, GWASs were performed on NAFLD cases and controls and case-only analyses using histologic scores and liver function tests adjusting for age, sex, site, ancestry, PC, and body mass index (BMI).ResultsConsistent with previous results, a robust association was detected for the PNPLA3 gene cluster in participants with European ancestry. At the PNPLA3-SAMM50 region, three SNPs, rs738409, rs738408, and rs3747207, showed strongest association (best SNP rs738409 p=1.70x10(-20)). This effect was consistent in both pediatric (p=9.92x10(-6)) and adult (p=9.73x10(-15)) cohorts. Additionally, this variant was also associated with disease severity and NAFLD Activity Score (NAS) (p=3.94x10(-8), beta=0.85). PheWAS analysis link this locus to a spectrum of liver diseases beyond NAFLD with a novel negative correlation with gout (p=1.09x10(-4)). We also identified novel loci for NAFLD disease severity, including one novel locus for NAS score near IL17RA (rs5748926, p=3.80x10(-8)), and another near ZFP90-CDH1 for fibrosis (rs698718, p=2.74x10(-11)). Post-GWAS and gene-based analyses identified more than 300 genes that were used for functional and pathway enrichment analyses.ConclusionsIn summary, this study demonstrates clear confirmation of a previously described NAFLD risk locus and several novel associations. Further collaborative studies including an ethnically diverse population with well-characterized liver histologic features of NAFLD are needed to further validate the novel findings.

引用

页数：19

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