Query: liver genome wide

title: Genome wide association study of non alcoholic fatty liver and steatohepatitis in a histologically characterised cohort.
abstract: Genetic factors associated with non alcoholic fatty liver disease (NAFLD) remain incompletely understood. To date, most GWAS studies have adopted radiologically assessed hepatic triglyceride content as reference phenotype and so cannot address steatohepatitis or fibrosis. We describe a genome wide association study (GWAS) encompassing the full spectrum of histologically characterized NAFLD.  The GWAS involved 1483 European NAFLD cases and 17781 genetically matched population controls. A replication cohort of 559 NAFLD cases and 945 controls was genotyped to confirm signals showing genome wide or close to genome wide significance.  Case control analysis identified signals showing p values 5 x 10 8 at four locations (chromosome (chr) 2 GCKR/C2ORF16; chr4 HSD17B13; chr19 TM6SF2; chr22 PNPLA3) together with two other signals with p<1 x10 7 (chr1 near LEPR and chr8 near IDO2/TC1) Case only analysis of quantitative traits steatosis, disease activity score, NAS and fibrosis showed that the PNPLA3 signal (rs738409) was genome wide significantly associated with steatosis, fibrosis and NAS score and identified a new signal (PYGO1 rs62021874) with close to genome wide significance for steatosis (p=8.2 x 10 8) Subgroup case control analysis for NASH confirmed the PNPLA3 signal. The chr1 LEPR SNP also showed genome wide significance for this phenotype. Considering the subgroup with advanced fibrosis =F3) the signals on chromosomes 2, 19 and 22 remained genome wide significant. With the exception of GCKR/C2ORF16, the genome wide significant signals replicated.  This study confirms PNPLA3 as a risk factor for the full histological spectrum of NAFLD at genome wide significance levels, with important contributions from TM6SF2 and HSD17B13. PYGO1 is a novel steatosis modifier, suggesting relevance of Wnt signalling pathways in NAFLD pathogenesis.

title: Genome wide and Mendelian randomisation studies of liver MRI yield insights into the pathogenesis of steatohepatitis
abstract: MRI based corrected T1 (cT1) is a non invasive method to grade the severity of steatohepatitis and liver fibrosis. We aimed to identify genetic variants influencing liver cT1 and use genetics to understand mechanisms underlying liver fibroinflammatory disease and its link with other metabolic traits and diseases.  First, we performed a genome wide association study (GWAS) in 14,440 Europeans, with liver cT1 measures, from the UK Biobank. Second, we explored the effects of the cT1 variants on liver blood tests, and a range of metabolic traits and diseases. Third, we used Mendelian randomisation to test the causal effects of 24 predominantly metabolic traits on liver cT1 measures.  We identified 6 independent genetic variants associated with liver cT1 that reached the GWAS significance threshold (p <5x10 8) Four of the variants (rs759359281 in SLC30A10, rs13107325 in SLC39A8, rs58542926 in TM6SF2, rs738409 in PNPLA3) were also associated with elevated aminotransferases and had variable effects on liver fat and other metabolic traits. Insulin resistance, type 2 diabetes, non alcoholic fatty liver and body mass index were causally associated with elevated cT1, whilst favourable adiposity (instrumented by variants associated with higher adiposity but lower risk of cardiometabolic disease and lower liver fat) was found to be protective.  The association between 2 metal ion transporters and cT1 indicates an important new mechanism in steatohepatitis. Future studies are needed to determine whether interventions targeting the identified transporters might prevent liver disease in at risk individuals.  We estimated levels of liver inflammation and scarring based on magnetic resonance imaging of 14,440 UK Biobank participants. We performed a genetic study and identified variations in 6 genes associated with levels of liver inflammation and scarring. Participants with variations in 4 of these genes also had higher levels of markers of liver cell injury in blood samples, further validating their role in liver health. Two identified genes are involved in the transport of metal ions in our body. Further investigation of these variations may lead to better detection, assessment, and/or treatment of liver inflammation and scarring.

title: Genome Wide Association Study of Liver Fat: The Multiethnic Cohort Adiposity Phenotype Study
abstract: The global rise in fatty liver is a major public health problem. Thus, it is critical to identify both global and population specific genetic variants associated with liver fat. We conducted a genome wide association study (GWAS) of percent liver fat and nonalcoholic fatty liver disease (NAFLD) assessed by magnetic resonance imaging in 1,709 participants from the population based Multiethnic Cohort Adiposity Phenotype Study. Our participants comprised older adults of five U.S. racial/ethnic groups: African Americans (n 277) Japanese Americans (n 424) Latinos (n 348) Native Hawaiians (n 274) and European Americans (n 386) The established missense risk variant rs738409 located in patatin like phospholipase domain containing 3 (PNPLA3) at 22q13 was confirmed to be associated with percent liver fat (P 3.52 x 10 15) but more strongly in women than men (P heterogeneity 0.002) Its frequency correlated with the prevalence of NAFLD across the five ethnic/racial groups. Rs738409 was also associated with homeostasis model assessment of insulin resistance (HOMA IR) (beta 0.028; P 0.009) and circulating levels of insulin (beta 0.022; P 0.020) and alanine aminotransferase (beta 0.016; P 0.030) A novel association of percent liver fat with rs77249491 (located at 6q13 between limb region 1 domain containing 1 [LMBRD1] and collagen type XIX alpha 1 chain [COL19A1] (P 1.42 x 10 8) was also observed. Rs7724941 was associated with HOMA IR (beta 0.12; P 0.0005) insulin (beta 0.11; P 0.0003) triglycerides (beta 0.059; P 0.01) high density lipoprotein (beta 0.046; P 0.04) and sex hormone binding globulin (beta 0.084; P 0.0012) This variant was present in Japanese Americans (minor allele frequency [MAF] 8% and Native Hawaiians (MAF, 2%  We replicated the PNPLA3 rs738409 association in a multiethnic population and identified a novel liver fat risk variant in Japanese Americans and Native Hawaiians. GWASes of percent liver fat in East Asian and Oceanic populations are needed to replicate the rs77249491 association.

title: Genome wide pQTL analysis of protein expression regulatory networks in the human liver
abstract: Previous expression quantitative trait loci (eQTL) studies have identified thousands of genetic variants to be associated with gene expression at the mRNA level in the human liver. However, protein expression often correlates poorly with mRNA levels. Thus, protein quantitative trait loci (pQTL) study is required to identify genetic variants that regulate protein expression in human livers.  We conducted a genome wide pQTL study in 287 normal human liver samples and identified 900 local pQTL variants and 4026 distant pQTL variants. We further discovered 53 genome hotspots of pQTL variants. Transcriptional region mapping analysis showed that 1133 pQTL variants are in transcriptional regulatory regions. Genomic region enrichment analysis of the identified pQTL variants revealed 804 potential regulatory interactions among 595 predicted regulators (e.g. non coding RNAs) and 394 proteins. Moreover, pQTL variants and trait variant integration analysis implied several novel mechanisms underlying the relationships between protein expression and liver diseases, such as alcohol dependence. Notably, over 2000 of the identified pQTL variants have not been reported in previous eQTL studies, suggesting extensive involvement of genetic polymorphisms in post transcriptional regulation of protein expression in human livers.  We have partially established protein expression regulation networks in human livers and generated a wealth of pQTL data that could serve as a valuable resource for the scientific community.

title: A genome wide association study on liver enzymes in Korean population
abstract: Although genetic features vary across ethnicities, few genome wide association studies (GWAS) have reported the genetic determinants of liver enzyme expression. This study was aimed to evaluate the associations of genome wide single nuclear polymorphisms (SNPs) with the liver enzymes in a Korean population.  We performed a GWAS to identify genetic loci influencing liver function, as measured by concentrations of alkaline phosphatase (ALP) alanine transaminase (ALT) gamma glutamyl transferase (GGT) and total bilirubin (BIL) in in Korean study participants.  A total of 6,488 subjects (4,457 in the discovery and 2,031 in the validation set) were included. The mean subject age was 50.0+ 10.6 years (male, 53.7% Among a total of 546,738 SNPs tested, rs651007 and rs579459 located in the ABO gene showed strong associations with ALP (P 1.63x10 8 and 5.61x10 8, respectively [discovery set] P 4.08x10 15 and 9.92x10 16, respectively [validation set] Additionally, rs5751901 and rs2006092, which are located in the GGT1 gene, showed strong associations with GGT (P 6.44x10 15 and 1.26x10 15, respectively [discovery set] P 4.13x10 10 and 5.15x10 11, respectively [validation set] Among the 13 SNPs that showed genome wide significance with total bilirubin levels, rs10929302 and rs6742078 showed the most significant association (P 3.08x10 64 and 2.05x10 62, respectively [discovery set] P 1.33x10 116 and 2.24x10 118, respectively [validation set] No genome wide significant associations was found for ALT.  We demonstrated that ABO, GGT1 and UGT1A family were associated with ALP, GGT and BIL, respectively in Korean population. These findings differ from reported results in GWAS in European populations in terms of associated genes and locations, suggesting different genetic mechanisms of liver enzyme regulation according to ethnicity.

title: A genome wide association study for nonalcoholic fatty liver disease identifies novel genetic loci and trait relevant candidate genes in the Million Veteran Program.
abstract: Nonalcoholic fatty liver disease (NAFLD) is a prevalent, heritable trait that can progress to cancer and liver failure. Using our recently developed proxy definition for NAFLD based on chronic liver enzyme elevation without other causes of liver disease or alcohol misuse, we performed a multi ancestry genome wide association study in the Million Veteran Program with 90,408 NAFLD cases and 128,187 controls. Seventy seven loci exceeded genome wide significance of which 70 were novel, with an additional European American specific and two African American specific loci. Twelve of these loci were also significantly associated with quantitative hepatic fat on radiological imaging (n=44,289) Gene prioritization based on coding annotations, gene expression from GTEx, and functional genomic annotation identified candidate genes at 97% of loci. At eight loci, the allele associated with lower gene expression in liver was also associated with reduced risk of NAFLD, suggesting potential therapeutic relevance. Functional genomic annotation and gene set enrichment demonstrated that associated loci were relevant to liver biology. We expand the catalog of genes influencing NAFLD, and provide a novel resource to understand its disease initiation, progression and therapy.

title: Genome wide copy number analysis of circulating tumor cells in breast cancer patients with liver metastasis
abstract: The genome wide copy number analysis of circulating tumor cells (CTCs) provides a promising prognostic biomarker for survival in breast cancer liver metastasis (BCLM) patients. The present study aimed to confirm the prognostic value of the presence of CTCs in BCLM patients. We previously developed an assay for the genome wide pattern differences in copy number variations (CNVs) as an adjunct test for the routine imaging and histopathologic diagnosis methods to distinguish newly diagnosed liver metastases and recurrent liver metastases. Forty three breast cancer patients were selected for this study in which 23 newly diagnosed and 20 recurrent liver metastases were diagnosed by histopathology and 18F FDG PET/CT imaging. CTCs were counted from all patients using the CellSearch system and were confirmed by cytomorphology and three color immunocytochemistry. Genomic DNA of single CTCs was amplified using multiple annealing and looping based amplification cycles (MALBAC) Then, we compared the CTC numbers of newly diagnosed and recurrent BCLM patients using Illumina platforms. A high CTC frequency >15 CTCs/7.5 ml blood) was found to be correlated with disease severity and metastatic progression, which suggests the value for CTCs in the diagnosis of BCLM in comparison with pathohistology and PET/CT imaging (P>0.05) Moreover, CTCs isolated from BCLM patients remained an independent prognostic detection factor associated with overall survival (P=0.0041) Comparison between newly diagnosed and recurrent liver metastases revealed different frequencies of CNVs (P>0.05) Notably, the CNV pattern of isolated CTCs of recurrent BCLM patients was similar to recurrent liver metastases (nearly 82% of the gain/loss regions) Functional enrichment analysis identified 25 genes as a CNV signature of BCLM. Among them, were defensin and b defensin genes, which are significantly associated with anti angiogenesis and immunomodulation signaling pathways. High CTC frequencies are effective in the evaluation and differentiation between newly diagnosed liver metastases from recurrent liver metastases. Future clinical studies will be necessary to fully determine the prognostic potential of CTC cluster signatures in patients with BCLM.

title: Genome wide association study of circulating liver enzymes reveals an expanded role for manganese transporter SLC30A10 in liver health
abstract: To better understand molecular pathways underlying liver health and disease, we performed genome wide association studies (GWAS) on circulating levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) across 408,300 subjects from four ethnic groups in the UK Biobank, focusing on variants associating with both enzymes. Of these variants, the strongest effect is a rare (MAF in White British 0.12% missense variant in the gene encoding manganese efflux transporter SLC30A10, Thr95Ile (rs188273166) associating with a 5.9% increase in ALT and a 4.2% increase in AST. Carriers have higher prevalence of all cause liver disease (OR 1.70; 95% CI 1.24 to 2.34) and higher prevalence of extrahepatic bile duct cancer (OR 23.8; 95% CI 9.1 to 62.1) compared to non carriers. Over 4% of the cases of extrahepatic cholangiocarcinoma in the UK Biobank carry SLC30A10 Thr95Ile. Unlike variants in SLC30A10 known to cause the recessive syndrome hypermanganesemia with dystonia 1 (HMNDYT1) the Thr95Ile variant has a detectable effect even in the heterozygous state. Also unlike HMNDYT1 causing variants, Thr95Ile results in a protein that is properly trafficked to the plasma membrane when expressed in HeLa cells. These results suggest that coding variation in SLC30A10 impacts liver health in more individuals than the small population of HMNDYT1 patients.

title: Genome Wide Association Study of Lean Nonalcoholic Fatty Liver Disease Suggests Human Leukocyte Antigen as a Novel Candidate Locus
abstract: Nonalcoholic fatty liver disease (NAFLD) is supposed to manifest its metabolic phenotype in the liver, but it is common to have lean individuals diagnosed with NAFLD, known as lean NAFLD. We conducted a two stage analysis to identify NAFLD associated loci in Japanese patients. In stage I, 275 metabolically healthy normal weight patients with NAFLD were compared with 1,411 non NAFLD controls adjusted for age, sex, and alcohol consumption by a genome wide association study (GWAS) In stage II, human leukocyte antigen (HLA) in chromosome 6 (chr6) (P 6.73E 08) microRNA (MIR) MIR548F3 in chr7 (P 4.25E 07) myosin light chain 2 (MYL2) in chr12 (P 4.39E 07) and glycoprotein precursor (GPC)6 in chr13 (P 5.43E 07) as suggested by the GWAS, were assessed by single nucleotide polymorphism (SNP) association analysis of whole NAFLD against non NAFLD in 9,726 members of the general population. A minor allele of the secondary lead SNP in chr6, rs2076529, was significantly associated (odds ratio [OR] 1.19; 95% confidence interval [CI] 1.11 1.28; P 2.10E 06) and the lead SNP in chr7 was weakly associated (OR 1.15; 95% CI, 1.04 1.27; P 6.19E 03) with increased NAFLD risk. Imputation based typing of HLA showed a significant difference in the distribution of HLA B, HLA DR beta chain 1 (DRB1) and HLA DQ beta chain 1 (DQB1) alleles in lean NAFLD GWAS. Next generation sequence based typing of HLA in 5,649 members of the general population replicated the significant difference of HLA B allele distribution and the significant increase of the HLA B*54:01 allele in whole NAFLD. Fecal metagenomic analysis of 3,420 members of the general population showed significant dissimilarity in beta diversity analysis of rs2076529 and HLA B*54:01 allele carriers from noncarriers. Veillonellaceae was increased but Verrucomicrobia was decreased in rs2076529 minor allele and HLA B*54:01 allele carriers as in NAFLD.  HLA was identified as a novel locus associated with NAFLD susceptibility, which might be affected by the alteration of gut microbiota.

title: A genome wide CRISPR Cas9 screen identifies CENPJ as a host regulator of altered microtubule organization during Plasmodium liver infection
abstract: Prior to initiating symptomatic malaria, a single Plasmodium sporozoite infects a hepatocyte and develops into thousands of merozoites, in part by scavenging host resources. We show that host microtubules dynamically reorganize around the developing liver stage (LS) parasite. Using a genome wide CRISPR Cas9 screen, we identified host regulators of cytoskeleton organization, vesicle trafficking, ER/Golgi stress and lipid biogenesis that regulate Plasmodium LS development. These novel regulators of infection, including Centromere Protein J (CENPJ) led us to interrogate how microtubule organizing centers (MTOCs) are regulated during infection. Foci of g tubulin localized to the parasite periphery; depletion of CENPJ exacerbated this re localization and increased infection. Further, we show that the Golgi acts as a non centrosomal MTOC by organizing g tubulin and stimulating microtubule nucleation at the parasite periphery. Collectively, we show that the Plasmodium LS recruits the host Golgi to form MT mediated conduits along which host organelles are recruited to the PVM, to support liver stage development. Our findings suggest many host targeted pharmacological inhibitors may inhibit LS infection.