Genetic variants that associate with cirrhosis have pleiotropic effects on human traits

Background and AimsCirrhosis is characterized by extensive fibrosis of the liver and is a major cause of liver‐related mortality. Cirrhosis is partially heritable but genetic contributions to cirrhosis have not been systemically explored. Here, we carry out association analyses with cirrhosis in two large biobanks and determine the effects of cirrhosis associated variants on multiple human disease/traits.MethodsWe carried out a genome‐wide association analysis of cirrhosis as a diagnosis in UK BioBank (UKBB; 1088 cases vs. 407 873 controls) and then tested top‐associating loci for replication with cirrhosis in a hospital‐based cohort from the Michigan Genomics Initiative (MGI; 875 cases of cirrhosis vs. 30 346 controls). For replicating variants or variants previously associated with cirrhosis that also affected cirrhosis in UKBB or MGI, we determined single nucleotide polymorphism effects on all other diagnoses in UKBB (PheWAS), common metabolic traits/diseases and serum/plasma metabolites.ResultsUnbiased genome‐wide association study identified variants in/near PNPLA3 and HFE, and candidate variant analysis identified variants in/near TM6SF2, MBOAT7, SERPINA1, HSD17B13, STAT4 and IFNL4 that reproducibly affected cirrhosis. Most affected liver enzyme concentrations and/or aspartate transaminase‐to‐platelet ratio index. PheWAS, metabolic trait and serum/plasma metabolite association analyses revealed effects of these variants on lipid, inflammatory and other processes including new effects on many human diseases and traits.ConclusionsWe identified eight loci that reproducibly associate with population‐based cirrhosis and define their diverse effects on human diseases and traits.See Editorial on Page 281Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153621/1/liv14321_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153621/2/liv14321.pd

Independent markers of nonalcoholic fatty liver disease in a gentrifying population‐based Chinese cohort

BackgroundPrevalence of nonalcoholic fatty liver disease (NAFLD) is increasing in developing countries, but its causes are not known. We aimed to ascertain the prevalence and determinants of NAFLD in a new largely unmedicated population‐based cohort from the rapidly gentrifying region of Pinggu, China.MethodsWe randomized cluster sampled 4002 Pinggu residents aged 26 to 76 years. Data from 1238 men and 1928 women without significant alcohol drinking or hepatitis virus B or C infection were analysed. NAFLD was defined using a liver‐spleen ratio (L/S ratio) ≤1.1 on unenhanced abdominal computed tomography (CT) scanning.ResultsOf men and women, 26.5% and 20.1%, respectively, had NAFLD. NAFLD prevalence was highest in younger men and older women. In multivariate logistic regression models, higher body mass index, waist circumference, serum triglyceride, alanine transaminase, and haemoglobin A1c independently increased the odds of NAFLD in both men and women separately. Higher annual household income and systolic blood pressure for men and higher serum uric acid and red meat intake and lower physical activity levels for women also independently associated with higher odds of NAFLD. Individuals with L/S ratio ≤1.1 had linearly increasing rates of obesity, diabetes, and metabolic syndrome that paralleled fatty liver increase.ConclusionsNAFLD is common in a gentrifying Chinese population particularly in younger men of high socioeconomic status and older women with sedentary behaviour who eat red meat. Demographic factors add independent risk of NAFLD above traditional metabolic risk factors. A CT L/S ratio of ≤1.1 identifies individuals at high risk of metabolic disease.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149708/1/dmrr3156_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149708/2/dmrr3156.pd

Body Composition and Genetic Lipodystrophy Risk Score Associate With Nonalcoholic Fatty Liver Disease and Liver Fibrosis

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150618/1/hep41391.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150618/2/hep41391_am.pd

Genomeâ Wide Study of Subcutaneous and Visceral Adipose Tissue Reveals Novel Sexâ Specific Adiposity Loci in Mexican Americans

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141319/1/oby22074.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141319/2/oby22074_am.pd

17‐Beta Hydroxysteroid Dehydrogenase 13 Is a Hepatic Retinol Dehydrogenase Associated With Histological Features of Nonalcoholic Fatty Liver Disease

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/148371/1/hep30350.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148371/2/hep30350_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148371/3/hep30350-sup-0001-Supinfo.pd

Adipose Tissue Depots and Their Cross‐Sectional Associations With Circulating Biomarkers of Metabolic Regulation

Background: Visceral adipose tissue (VAT) and fatty liver differ in their associations with cardiovascular risk compared with subcutaneous adipose tissue (SAT). Several biomarkers have been linked to metabolic derangements and may contribute to the pathogenicity of fat depots. We examined the association between fat depots on multidetector computed tomography and metabolic regulatory biomarkers. Methods and Results: Participants from the Framingham Heart Study (n=1583, 47% women) underwent assessment of SAT, VAT, and liver attenuation. We measured circulating biomarkers secreted by adipose tissue or liver (adiponectin, leptin, leptin receptor, fatty acid binding protein 4, fetuin‐A, and retinol binding protein 4). Using multivariable linear regression models, we examined relations of fat depots with biomarkers. Higher levels of fat depots were positively associated with leptin and fatty acid binding protein 4 but negatively associated with adiponectin (all P<0.001). Associations with leptin receptor, fetuin‐A, and retinol binding protein 4 varied according to fat depot type or sex. When comparing the associations of SAT and VAT with biomarkers, VAT was the stronger correlate of adiponectin (β=−0.28 [women]; β=−0.30 [men]; both P<0.001), whereas SAT was the stronger correlate of leptin (β=0.62 [women]; β=0.49 [men]; both P<0.001; P<0.001 for comparing VAT versus SAT). Although fetuin‐A and retinol binding protein 4 are secreted by the liver in addition to adipose tissue, associations of liver attenuation with these biomarkers was not stronger than that of SAT or VAT. Conclusions: SAT, VAT, and liver attenuation are associated with metabolic regulatory biomarkers with differences in the associations by fat depot type and sex. These findings support the possibility of biological differences between fat depots

The Metabochip, a Custom Genotyping Array for Genetic Studies of Metabolic, Cardiovascular, and Anthropometric Traits

PMCID: PMC3410907This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Insulin Resistance Exacerbates Genetic Predisposition to Nonalcoholic Fatty Liver Disease in Individuals Without Diabetes

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149741/1/hep41353.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149741/2/hep41353_am.pd

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.