Two obsessive-compulsive disorder (OCD) genome-wide association studies (GWASs) have been published by independent OCD consortia, the International Obsessive-Compulsive Disorder Foundation Genetics ...Collaborative (IOCDF-GC) and the OCD Collaborative Genetics Association Study (OCGAS), but many of the top-ranked signals were supported in only one study. We therefore conducted a meta-analysis from the two consortia, investigating a total of 2688 individuals of European ancestry with OCD and 7037 genomically matched controls. No single-nucleotide polymorphisms (SNPs) reached genome-wide significance. However, in comparison with the two individual GWASs, the distribution of P-values shifted toward significance. The top haplotypic blocks were tagged with rs4733767 (P=7.1 × 10
; odds ratio (OR)=1.21; confidence interval (CI): 1.12-1.31, CASC8/CASC11), rs1030757 (P=1.1 × 10
; OR=1.18; CI: 1.10-1.26, GRID2) and rs12504244 (P=1.6 × 10
; OR=1.18; CI: 1.11-1.27, KIT). Variants located in or near the genes ASB13, RSPO4, DLGAP1, PTPRD, GRIK2, FAIM2 and CDH20, identified in linkage peaks and the original GWASs, were among the top signals. Polygenic risk scores for each individual study predicted case-control status in the other by explaining 0.9% (P=0.003) and 0.3% (P=0.0009) of the phenotypic variance in OCGAS and the European IOCDF-GC target samples, respectively. The common SNP heritability in the combined OCGAS and IOCDF-GC sample was estimated to be 0.28 (s.e.=0.04). Strikingly, ∼65% of the SNP-based heritability in the OCGAS sample was accounted for by SNPs with minor allele frequencies of ⩾40%. This joint analysis constituting the largest single OCD genome-wide study to date represents a major integrative step in elucidating the genetic causes of OCD.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Obsessive–compulsive disorder (OCD) is a highly heritable complex phenotype that demonstrates sex differences in age of onset and clinical presentation, suggesting a possible sex difference in ...underlying genetic architecture. We present the first genome‐wide characterization of the sex‐specific genetic architecture of OCD, utilizing the largest set of OCD cases and controls available from the Psychiatric Genomics Consortium. We assessed evidence for several mechanisms that may contribute to sex differences including a sex‐dependent liability threshold, the presence of individual sex‐specific risk variants on the autosomes and the X chromosome, and sex‐specific pleiotropic effects. Furthermore, we tested the hypothesis that genetic heterogeneity between the sexes may obscure associations in a sex‐combined genome‐wide association study. We observed a strong genetic correlation between male and female OCD and no evidence for a sex‐dependent liability threshold model, suggesting that sex‐combined analysis does not suffer from widespread loss of power because of genetic heterogeneity between the sexes. While we did not detect any significant sex‐specific genome‐wide single nucleotide polymorphisms (SNP) associations, we did identify two significant gene‐based associations in females: GRID2 and GRP135, which showed no association in males. We observed that the SNPs with sexually differentiated effects showed an enrichment of regulatory variants influencing expression of genes in brain and immune tissues. These findings suggest that future studies with larger sample sizes hold great promise for the identification of sex‐specific genetic risk factors for OCD.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Using a novel trait-based measure, we examined genetic variants associated with obsessive-compulsive (OC) traits and tested whether OC traits and obsessive-compulsive disorder (OCD) shared genetic ...risk. We conducted a genome-wide association analysis (GWAS) of OC traits using the Toronto Obsessive-Compulsive Scale (TOCS) in 5018 unrelated Caucasian children and adolescents from the community (Spit for Science sample). We tested the hypothesis that genetic variants associated with OC traits from the community would be associated with clinical OCD using a meta-analysis of all currently available OCD cases. Shared genetic risk was examined between OC traits and OCD in the respective samples using polygenic risk score and genetic correlation analyses. A locus tagged by rs7856850 in an intron of PTPRD (protein tyrosine phosphatase δ) was significantly associated with OC traits at the genome-wide significance level (p = 2.48 × 10
). rs7856850 was also associated with OCD in a meta-analysis of OCD case/control genome-wide datasets (p = 0.0069). The direction of effect was the same as in the community sample. Polygenic risk scores from OC traits were significantly associated with OCD in case/control datasets and vice versa (p's < 0.01). OC traits were highly, but not significantly, genetically correlated with OCD (r
= 0.71, p = 0.062). We report the first validated genome-wide significant variant for OC traits in PTPRD, downstream of the most significant locus in a previous OCD GWAS. OC traits measured in the community sample shared genetic risk with OCD case/control status. Our results demonstrate the feasibility and power of using trait-based approaches in community samples for genetic discovery.
The hepatic tricarboxylic acid (TCA) cycle is central to integrating macronutrient metabolism and is closely coupled to cellular respiration, free radical generation, and inflammation. Oxidative flux ...through the TCA cycle is induced during hepatic insulin resistance, in mice and humans with simple steatosis, reflecting early compensatory remodeling of mitochondrial energetics. We hypothesized that progressive severity of hepatic insulin resistance and the onset of nonalcoholic steatohepatitis (NASH) would impair oxidative flux through the hepatic TCA cycle. Mice (C57/BL6) were fed a high-trans-fat high-fructose diet (TFD) for 8 wk to induce simple steatosis and NASH by 24 wk. In vivo fasting hepatic mitochondrial fluxes were determined by(13)C-nuclear magnetic resonance (NMR)-based isotopomer analysis. Hepatic metabolic intermediates were quantified using mass spectrometry-based targeted metabolomics. Hepatic triglyceride accumulation and insulin resistance preceded alterations in mitochondrial metabolism, since TCA cycle fluxes remained normal during simple steatosis. However, mice with NASH had a twofold induction (P< 0.05) of mitochondrial fluxes (μmol/min) through the TCA cycle (2.6 ± 0.5 vs. 5.4 ± 0.6), anaplerosis (9.1 ± 1.2 vs. 16.9 ± 2.2), and pyruvate cycling (4.9 ± 1.0 vs. 11.1 ± 1.9) compared with their age-matched controls. Induction of the TCA cycle activity during NASH was concurrent with blunted ketogenesis and accumulation of hepatic diacylglycerols (DAGs), ceramides (Cer), and long-chain acylcarnitines, suggesting inefficient oxidation and disposal of excess free fatty acids (FFA). Sustained induction of mitochondrial TCA cycle failed to prevent accretion of "lipotoxic" metabolites in the liver and could hasten inflammation and the metabolic transition to NASH.
Assess the prevalence of nonalcoholic fatty liver disease (NAFLD) and of liver fibrosis associated with nonalcoholic steatohepatitis in unselected patients with type 2 diabetes mellitus (T2DM).
A ...total of 561 patients with T2DM (age: 60 ± 11 years; BMI: 33.4 ± 6.2 kg/m
; and HbA
: 7.5 ± 1.8%) attending primary care or endocrinology outpatient clinics and unaware of having NAFLD were recruited. At the visit, volunteers were invited to be screened by elastography for steatosis and fibrosis by controlled attenuation parameter (≥274 dB/m) and liver stiffness measurement (LSM; ≥7.0 kPa), respectively. Secondary causes of liver disease were ruled out. Diagnostic panels for prediction of advanced fibrosis, such as AST-to-platelet ratio index (APRI) and Fibrosis-4 (FIB-4) index, were also measured. A liver biopsy was performed if results were suggestive of fibrosis.
The prevalence of steatosis was 70% and of fibrosis 21% (LSM ≥7.0 kPa). Moderate fibrosis (F2: LSM ≥8.2 kPa) was present in 6% and severe fibrosis or cirrhosis (F3-4: LSM ≥9.7 kPa) in 9%, similar to that estimated by FIB-4 and APRI panels. Noninvasive testing was consistent with liver biopsy results. Elevated AST or ALT ≥40 units/L was present in a minority of patients with steatosis (8% and 13%, respectively) or with liver fibrosis (18% and 28%, respectively). This suggests that AST/ALT alone are insufficient as initial screening. However, performance may be enhanced by imaging (e.g., transient elastography) and plasma diagnostic panels (e.g., FIB-4 and APRI).
Moderate-to-advanced fibrosis (F2 or higher), an established risk factor for cirrhosis and overall mortality, affects at least one out of six (15%) patients with T2DM. These results support the American Diabetes Association guidelines to screen for clinically significant fibrosis in patients with T2DM with steatosis or elevated ALT.
Objective:Obsessive-compulsive disorder (OCD) and Tourette’s syndrome are highly heritable neurodevelopmental disorders that are thought to share genetic risk factors. However, the identification of ...definitive susceptibility genes for these etiologically complex disorders remains elusive. The authors report a combined genome-wide association study (GWAS) of Tourette’s syndrome and OCD.Method:The authors conducted a GWAS in 2,723 cases (1,310 with OCD, 834 with Tourette’s syndrome, 579 with OCD plus Tourette’s syndrome/chronic tics), 5,667 ancestry-matched controls, and 290 OCD parent-child trios. GWAS summary statistics were examined for enrichment of functional variants associated with gene expression levels in brain regions. Polygenic score analyses were conducted to investigate the genetic architecture within and across the two disorders.Results:Although no individual single-nucleotide polymorphisms (SNPs) achieved genome-wide significance, the GWAS signals were enriched for SNPs strongly associated with variations in brain gene expression levels (expression quantitative loci, or eQTLs), suggesting the presence of true functional variants that contribute to risk of these disorders. Polygenic score analyses identified a significant polygenic component for OCD (p=2×10−4), predicting 3.2% of the phenotypic variance in an independent data set. In contrast, Tourette’s syndrome had a smaller, nonsignificant polygenic component, predicting only 0.6% of the phenotypic variance (p=0.06). No significant polygenic signal was detected across the two disorders, although the sample is likely underpowered to detect a modest shared signal. Furthermore, the OCD polygenic signal was significantly attenuated when cases with both OCD and co-occurring Tourette’s syndrome/chronic tics were included in the analysis (p=0.01).Conclusions:Previous work has shown that Tourette’s syndrome and OCD have some degree of shared genetic variation. However, the data from this study suggest that there are also distinct components to the genetic architectures of these two disorders. Furthermore, OCD with co-occurring Tourette’s syndrome/chronic tics may have different underlying genetic susceptibility compared with OCD alone.
Dysfunctional mitochondrial function plays an important role in the progression of nonalcoholic steatohepatitis (NASH). Mitochondrial (mt) respiratory function assessed by oxidative phosphorylation/ ...OXPHOS (activated respiration with mt complex I OXPHOS CI and mt complex I + II OXPHOS CI+II substrates) and electron transport system capacity ETC were measured using high-resolution respirometry (Oroboros Oxygraph 2k). The aim of this study was to assess mitochondrial function in patients a) with vs. without NASH, and b) NASH with vs. without fibrosis. Liver tissue was obtained from 40 patients (age: 52 ± 12 yrs; BMI: 39.4 ± 8.4 kg/m2; HbA1c: 6.9 ± 1.5%) with NAFLD and obesity or T2DM either by percutaneous liver biopsy (n=28) or during bariatric surgery (n=12). Patients with vs. without NASH (n=20 in each group) were more insulin resistant/ IR (HOMA-IR: 8.1 ± 4.2 vs. 4.5 ± 2.7 mg/dl x μU/ml; Adipo-IR: 10.4 ± 7.2 vs. 6.2 ± 3.8 mmol/L x µU/mL) and had higher OXPHOS CI+II (all p<0.05), likely an adaptation to IR and higher FFA flux to the liver. We then compared those with worse steatohepatitis (necroinflammation score/ NIS), divided as mild (n=16), moderate (n=15) or severe (n=9). Patients with moderate vs. mild NIS had increased mitochondrial respiration, expressed as pmol/(s x mg wet weight) (OXPHOS CI: 20.8 ± 4.8 vs. 16.4 ± 4.6; OXPHOS CI+II: 46.0 ± 11.4 vs. 31.3 ± 9.8; ETC: 60.5 ± 17.1 vs. 46.4 ± 15.2; all p<0.05). There was a trend for these parameters to decline with the most severe disease activity, that was significant when patients with NASH also had significant fibrosis vs. mild or no fibrosis (OXPHOS CI+II: 38.6 ± 7.8 vs. 49.8 ± 12.5, p=0.04; ETC: 50.3 ± 12.9 vs. 67.5 ± 16.1; p=0.02).
Conclusion: In patients with NASH vs. simple steatosis, there is an early hepatic mitochondrial adaptation to severe insulin resistance. This adaptation is impaired when disease activity worsens, being most evident once patients develop steatohepatitis with significant fibrosis.
Disclosure
S. Kalavalapalli: None. D. Poulton: None. L. Mansour: None. S. Shrestha: None. F. Bril: None. S. K. Subbarayan: None. S. Kadiyala: None. K. Cusi: None. D. Barb: None. E. Godinez: None. R. Lomonaco: None. J. Friedman: Consultant; Self; Ethicon, Inc. S. Wohlgemuth: None. N. Fanous: None. R. E. Dillard: None. T. M. Cowan: None.
Abstract
Dysfunctional mitochondrial function is believed to play a vital role in the progression of nonalcoholic steatohepatitis (NASH) to advanced fibrosis and cirrhosis. However, most evidence ...arises from animal models while there is limited data in humans. The characteristic histological finding of NASH is hepatocellular injury with ballooning and inflammation, often associated with fibrosis in advanced disease. The aim of this study was to assess the role of mitochondrial function (eg, oxidative phosphorylation OXPHOS in patients with vs. without NASH and fibrosis. To this end, we recruited 38 patients with NAFLD with risk factors (obesity and/or type 2 diabetes) for NASH (age: 52±12 years; 37% male; BMI: 39.6±8.5 kg/m2; HbA1c: 6.8±1.4%) in whom we assessed mitochondrial respiration and also performed measurements of insulin resistance (IR). Tissue was obtained by either a Tru-cut percutaneous liver biopsy (n=26) or a wedge biopsy during bariatric surgery (n=12). After tissue was separated for histological diagnosis, small liver samples (2–4 mg) were processed to quantify OXPHOS by measuring the mitochondrial oxygen consumption rate in individual complexes of mitochondria, expressed as pmol×mg wet weight-1×s-1, using high-resolution respirometry, Oxygraph-2k. Based on liver histology, patients with NASH (n=18) compared to without NASH (n=20), had worse hyperinsulinemia and HOMA-IR (25.2±10.5 vs 14.9± 6.7 µU/ml and 8.9±4.3 vs. 4.9±2.9 mg/dl × µU/ml, respectively) and higher OXPHOS (all p<0.05), although well matched for age, BMI, HbA1c and % with diabetes. This was likely an adaptation to IR and higher FFA flux to the liver. We then examined patients based specifically on disease activity, using a combined score of hepatocyte ballooning and inflammation (necroinflammation score NIS) and divided as mild (n=16), moderate (n=14) or severe (n=8) NIS (also well matched for relevant clinical parameters). Patients in the moderate vs. mild NIS group disease activity had increased mitochondrial respiration as represented by OXPHOS (45.9±11.8 vs. 31.3±9.8), electron transport chain activity (ETC) (61.0±17.6 vs. 46.4±15.2) and state 3 respiration induced by ADP (20.7±4.9 vs. 16.4±4.6 pmol×mg wet weight-1×s-1; all p<0.05). There was a trend for these parameters to decline in patients with severe vs. moderate disease activity, that was further accentuated when patients with NASH also had clinically significant fibrosis compared to those with mild or no fibrosis (OXPHOS: 37.9±7.8 vs. 49.8±12.5, p=0.04; and ETC: 49.8±13.4 vs. 67.5±16.1, p=0.02). Conclusion: In patients with NASH, there is an early hepatic mitochondrial adaptation to account for the state of more severe insulin resistance in steatohepatitis compared to simple steatosis. This adaptation is impaired when disease activity worsens and is most evident once patients develop steatohepatitis with significant fibrosis.
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