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      Adiposity Amplifies the Genetic Risk of Fatty Liver Disease Conferred by Multiple Loci

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          Abstract

          Complex traits arise from the interplay between genetic and environmental factors. The actions of these factors usually appear to be additive, and few compelling examples of gene-environment synergy have been documented. Here we show that adiposity significantly amplifies the effect of three sequence variants (PNPLA3-I148M, TM6SF2-E167K and GCKR-P446L) associated with nonalcoholic fatty liver disease (NAFLD). Synergy between adiposity and genotype promoted the full spectrum of NAFLD, from steatosis to hepatic inflammation to cirrhosis. We found no evidence of strong interactions between adiposity and sequence variants influencing other adiposity-associated traits. These results indicate that adiposity may augment genetic risk of NAFLD at multiple loci through at least three different metabolic mechanisms.

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          Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease

          Stefano Romeo, Julia Kozlitina, Chao Xing … (2008)
          Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem of unknown etiology that varies in prevalence among ethnic groups. To identify genetic variants contributing to differences in hepatic fat content, we performed a genome-wide association scan of nonsynonymous sequence variations (n=9,229) in a multiethnic population. An allele in PNPLA3 (rs738409; I148M) was strongly associated with increased hepatic fat levels (P=5.9×10−10) and with hepatic inflammation (P=3.7×10−4). The allele was most common in Hispanics, the group most susceptible to NAFLD; hepatic fat content was > 2-fold higher in PNPLA3-148M homozygotes than in noncarriers. Resequencing revealed another allele associated with lower hepatic fat content in African-Americans, the group at lowest risk of NAFLD. Thus, variation in PNPLA3 contributes to ethnic and inter-individual differences in hepatic fat content and susceptibility to NAFLD.
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            The mystery of missing heritability: Genetic interactions create phantom heritability.

            O Zuk, E. Hechter, S. R. Sunyaev … (2012)
            Human genetics has been haunted by the mystery of "missing heritability" of common traits. Although studies have discovered >1,200 variants associated with common diseases and traits, these variants typically appear to explain only a minority of the heritability. The proportion of heritability explained by a set of variants is the ratio of (i) the heritability due to these variants (numerator), estimated directly from their observed effects, to (ii) the total heritability (denominator), inferred indirectly from population data. The prevailing view has been that the explanation for missing heritability lies in the numerator--that is, in as-yet undiscovered variants. While many variants surely remain to be found, we show here that a substantial portion of missing heritability could arise from overestimation of the denominator, creating "phantom heritability." Specifically, (i) estimates of total heritability implicitly assume the trait involves no genetic interactions (epistasis) among loci; (ii) this assumption is not justified, because models with interactions are also consistent with observable data; and (iii) under such models, the total heritability may be much smaller and thus the proportion of heritability explained much larger. For example, 80% of the currently missing heritability for Crohn's disease could be due to genetic interactions, if the disease involves interaction among three pathways. In short, missing heritability need not directly correspond to missing variants, because current estimates of total heritability may be significantly inflated by genetic interactions. Finally, we describe a method for estimating heritability from isolated populations that is not inflated by genetic interactions.
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              Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease

              Julia Kozlitina, Eriks Smagris, Stefan Stender … (2014)
              Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease. To elucidate the molecular basis of NAFLD we performed an exome-wide association study of liver fat content. Three variants were associated with increased liver fat at the exome-wide significance level: two in PNPLA3, an established locus for NAFLD, and one (Glu167Lys) in TM6SF2, a gene of unknown function. The Glu167LysTM6SF2 variant was also associated with higher circulating levels of alanine transaminase, a marker of liver injury, and lower levels of LDL-cholesterol, triglycerides and alkaline phosphatase in 3 independent populations (n>80,000). Recombinant Glu167LysTM6SF2 produced 50% less protein than wild-type TM6SF2 when expressed in cultured hepatocytes. Adeno-associated virus-mediated shRNA knockdown of Tm6sf2 in mice increased liver triglyceride content 3-fold and decreased VLDL secretion by 50%. Taken together, these data indicate that TM6SF2 activity is required for normal VLDL secretion, and that impaired TM6SF2 function causally contributes to NAFLD.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 9216904
                Journal ID (pubmed-jr-id): 2419
                Journal ID (nlm-ta): Nat Genet
                Journal ID (iso-abbrev): Nat. Genet.
                Title: Nature genetics
                ISSN (Print): 1061-4036
                ISSN (Electronic): 1546-1718
                Publication date Nihms-submitted: 21 June 2017
                Publication date (Electronic): 24 April 2017
                Publication date (Print): June 2017
                Publication date PMC-release: 24 October 2017
                Volume: 49
                Issue: 6
                Pages: 842-847
                Affiliations
                [1 ]Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA
                [2 ]McDermott Center for Human Growth & Development, University of Texas Southwestern Medical Center, Dallas, TX, USA
                [3 ]Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
                [4 ]Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark
                [5 ]The Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Denmark
                [6 ]The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark
                [7 ]Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
                [8 ]The Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX, USA
                Author notes
                Article
                Manuscript ID: NIHMS864885
                DOI: 10.1038/ng.3855
                PMC ID: 5562020
                PubMed ID: 28436986
                SO-VID: df7a3a5b-07b9-413f-b8e5-118a645a0c4c
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                Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

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                ScienceOpen disciplines: Genetics
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                ScienceOpen disciplines: Genetics

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