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Population-Based Genome-Wide Association Studies Reveal Six Loci Influencing Plasma Levels of Liver Enzymes

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Population-Based Genome-Wide Association Studies Reveal Six Loci Influencing Plasma Levels of Liver Enzymes REPORT Population-Based Genome-wide Association Studies Reveal Six Loci Influencing Plasma Levels of Liver Enzymes Xin Yuan,1 Dawn Waterworth,1 John R.B. Perry,3 Noha Lim,1 Kijoung Song,1 John C. Chambers,4 Weihua Zhang,4 Peter Vollenweider,5 Heide Stirnadel,2 Toby Johnson,6,7,8 Sven Bergmann,6,8 Noam D. Beckmann,6 Yun Li,12 Luigi Ferrucci,9 David Melzer,3 Dena Hernandez,10 Andrew Singleton,10 James Scott,11 Paul Elliott,4 Gerard Waeber,5 Lon Cardon,1 Timothy M. Frayling,3 Jaspal S. Kooner,11 and Vincent Mooser1,* Plasma liver-enzyme tests are widely used in the clinic for the diagnosis of liver diseases and for monitoring the response to drug treat- ment. There is considerable evidence that human genetic variation influences plasma levels of liver enzymes. However, such genetic variation has not been systematically assessed. In the present study, we performed a genome-wide association study of plasma liver-en- zyme levels in three populations (total n ¼ 7715) with replication in three additional cohorts (total n ¼ 4704). We identified two loci influencing plasma levels of alanine-aminotransferase (ALT) (CPN1-ERLIN1-CHUK on chromosome 10 and PNPLA3-SAMM50 on chro- mosome 22), one locus influencing gamma-glutamyl transferase (GGT) levels (HNF1A on chromosome 12), and three loci for alkaline phosphatase (ALP) levels (ALPL on chromosome 1, GPLD1 on chromosome 6, and JMJD1C-REEP3 on chromosome 10). In addition, we confirmed the associations between the GGT1 locus and GGT levels and between the ABO locus and ALP levels. None of the ALP-asso- ciated SNPs were associated with other liver tests, suggesting intestine and/or bone specificity. The mechanisms underlying the associ- ations may involve cis- or trans-transcriptional effects (some of the identified variants were associated with mRNA transcription in hu- man liver or lymphoblastoid cells), dysfunction of the encoded proteins (caused by missense variations at the functional domains), or other unknown pathways. These findings may help in the interpretation of liver-enzyme tests and provide candidate genes for liver dis- eases of viral, metabolic, autoimmune, or toxic origin. The specific associations with ALP levels may point to genes for bone or intestinal diseases. Plasma liver-enzyme tests are widely used in the clinic to these tests. Indeed, such information could assist in our identify patients with liver diseases, to monitor the course understanding of the interindividual differences in the and severity of these diseases and the effect of therapies, propensity for development of liver dysfunction in the and to detect drug-induced liver injury.1,2 These tests also presence of toxins or conditions such as metabolic syn- have substantial epidemiologic significance that extends drome. As such, identification of genes associated with beyond the liver, given that they have been shown to be liver-enzyme levels could reveal previously unsuspected prospective risk factors for type 2 diabetes, cardiovascular candidate genes for liver diseases of viral, metabolic, auto- disease, and all-cause mortality in multiple large stud- immune, or toxic origin. ies.3–6 Therefore, it is of interest to identify genes or loci af- The goal of the present study was to identify, by using fecting these markers in order to establish whether such a genome-wide association (GWA) approach, genes influ- loci are also associated with these clinical endpoints. encing plasma levels of ALT and aspartate-aminotransfer- Plasma liver-enzyme levels are influenced by environ- ase (AST), two markers of hepatocyte injury and liver fat mental and genetic factors. The estimated heritabilities accumulation, and of alkaline phosphatase (ALP) and range from 33% for alanine-aminotransferase (ALT) to GGT, used primarily as indicators of biliary or cholestatic 61% for gamma-glutamyl transferase (GGT).7,8 So far, diseases and heavy alcohol consumption. only a limited number of genes that influence liver- In the discovery phase, we carried out independent GWA enzyme levels have been identified, mostly those responsi- studies in three population-based cohorts, the CoLaus ble for Mendelian liver diseases such as mutations in the Study from Lausanne Switzerland11,12 (n ¼ 5636), the HFE gene in hemochromatosis (MIM 235200).9,10 A thor- InCHIANTI Study from Tuscany Italy13 (n ¼ 1200), and ough understanding of the genetic determinants of plasma a subset of the LOLIPOP Study from West London liver enzymes is important for proper interpretation of UK14,15 (n ¼ 879) (Table 1). The clinical characteristics of 1Genetics Division, GlaxoSmithKline, King of Prussia, PA 19406, USA; 2Worldwide Epidemiology, GlaxoSmithKline, Harlow EX2 5DW, UK; 3Genetics of Complex Traits, Institute of Biomedical and Clinical Sciences, Peninsula College of Medicine and Dentistry, University of Exeter, CM19 5AW, UK; 4Depart- ment of Epidemiology and Public Health, Imperial College London, London W2 11G, UK; 5Department of Medicine, CHUV University Hospital, Lausanne 1011, Switzerland; 6Division of Medical Genetics, CHUV University Hospital, Lausanne 1011, Switzerland; 7Institute for Social and Preventative Medicine, CHUV University Hospital, Lausanne 1011, Switzerland; 8Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland; 9Longitudinal Studies Section, Clinical Research Branch, Gerontology Research Center, National Institute of Aging, Baltimore, MD, USA; 10Laboratory of Neurogenetics, National Institute of Aging, Bethesda, MD 20892, USA; 11National Heart and Lung Institute, Imperial College London, London W12 0NN, UK; 12Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA *Correspondence: [email protected] DOI 10.1016/j.ajhg.2008.09.012. ª2008 by The American Society of Human Genetics. All rights reserved. 520 The American Journal of Human Genetics 83, 520–528, October 10, 2008 Table 1. Description of Six Collections Used in GWAS on Plasma Liver-Enzyme Levels CoLaus InCHIANTI LOLIPOP Sample size (n) 5636 1200 879 1006 1005 2693 Location Lausanne, Tuscany, Italy London, UK London, UK London, UK London, UK Switzerland Ethnicity European white European white European white Indian Asian European white Indian Asian Study Design Population-based Population-based Population-based Nested metabolic Nested metabolic Nested metabolic enriched with syndrome case syndrome case syndrome case coronary artery and control and control and control disease Data Usage GWA Discovery GWA Discovery GWA Discovery Replication Replication Replication Liver enzymes AST,a ALT,b GGT,c AST, ALT, ALT, GGT, ALP ALT, GGT, ALP ALT, GGT, ALP ALT, GGT, ALP and ALPd GGT, ALP Genotyping Affymetrix 500k Illumina Affymetrix 500k Perlegen, Perlegen, Illumina Platform HumanHap550 custom array custom array HumanHap300 Number of SNPs 370,697 496,032 387,549 248,537 266,722 317,968 genotyped a AST, aspartate aminotransferase. b ALT, alanine aminotransferase. c GGT, gamma-glutamyltransferase. d ALP, alkaline phosphatase. the participants are described in Table 2. The mean levels discovery and replication cohorts. The remaining 42 of liver-enzyme tests varied somewhat between popula- SNPs were not considered as replicated because of either tions, presumably because of slight differences in the de- lack of high-quality imputation (Appendix A) of the mographics of the populations under study and methodo- logical differences in the assays (Table S1 available online). Table 2. Clinical Characteristics of the Participants in the Accordingly, we used study-specific criteria for GWA-geno- 11,14 Discovery Data Sets from CoLaus, InCHIANTI, and LOLIPOP typing quality control and liver-enzyme-level analyses Population-Based Studies (Appendix A). Additional genotypes were imputed on the a a a basis of the HapMap Phase II data with the software CoLaus InCHIANTI LOLIPOP IMPUTE.16 For these imputed data, we performed associa- n 5636 1200 879b tion analysis with SNPTEST, using the full posterior proba- Sex (% F) 52.8 55.2 23.0 bility genotype distribution for each study separately Age (years) 53.2 5 10.8 68.4 5 15.9 52.8 5 10.4 Fasting glucose 5.56 5 1.16 5.24 5 1.36 5.50 5 1.54 (adding in relevant covariables). Only SNPs with a posterior (mmol/L) probability score >0.90, high genotype information con- Insulin (mIU/mL) 8.76 5 6.25 10.9 5 6.15 10.3 5 10.7 tent (proper_info >0.5), and minor allele frequency >0.01 BMI (kg/m2) 25.8 5 4.6 27.1 5 4.1 27.9 5 4.8 were considered for these imputed association analyses. Waist (cm) 89.3 5 13.4 NA 96.7 5 13.0 Quantile-quantile plots (Figure 1) revealed the presence Hip (cm) 101.0 5 9.3 NA 103.0 5 9.0 Total cholesterol 5.60 5 1.04 NA 5.32 5 1.07 of a substantial number of SNPs associated with ALT, (mmol/L) GGT, and ALP levels at a genome-wide significance level LDL-cholesterol 3.34 5 0.92 3.43 5 0.90 3.25 5 0.93 (p value < 10À7). No SNP with plasma levels of AST was as- (mmol/L) sociated with genome-wide significance. It is not clear why Triglycerides 1.40 5 1.20 1.42 5 0.88 1.61 5 1.16 AST was uninformative in this case. Highly significantly as- (mmol/L) HDL-cholesterol 1.64 5 0.44 1.43 5 0.39 1.36 5 0.35 sociated SNPs were located within discrete regions of the (mmol/L) genome (Figure 2), including two loci for ALT (10q24.2 Albumin (g/L) 44.2 5 2.5 42.3 5 3.2 43.6 5 2.9 and 22q13.31), two loci for GGT (12q24.31 and Smoking status 11.8 18.8 64.4 22q11.23), and five loci for ALP (1p36.12, 6p22.2, (% smokers) 9q34.13, 10q21.2-21.3, and 19q13.33). Alcohol 77.3 NA 75.7 consumption (%)c A total of 74 Affymetrix-genotyped SNPs (24 for ALT, 8 Type 2 Diabetes (%) 6.6 11.1 11.3 À5 for GGT, and 42 for ALP, Table S2) with a p value % 10 AST (U/L) 29.7 5 13.5 20.2 5 0.4 NA in the discovery phase was subsequently examined in ALT (U/L) 27.6 5 19.5 18.1 5 0.5 29.1 5 16.4 3699 Indian Asian and 1005 European white participants ALP (U/L) 63.4 5 20.4 204.2 5 71.5 80.9 5 38.5 from the LOLIPOP study (Table 1).
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