Genome-wide association study identifies RNF123 locus as associated with chronic widespread musculoskeletal pain

BACKGROUND AND OBJECTIVES: Chronic widespread musculoskeletal pain (CWP) is a symptom of fibromyalgia and a complex trait with poorly understood pathogenesis. CWP is heritable (48%–54%), but its genetic architecture is unknown and candidate gene studies have produced inconsistent results. We conducted a genome-wide association study to get insight into the genetic background of CWP. METHODS: Northern Europeans from UK Biobank comprising 6914 cases reporting pain all over the body lasting >3 months and 242 929 controls were studied. Replication of three independent genome-wide significant single nucleotide polymorphisms was attempted in six independent European cohorts (n=43 080; cases=14 177). Genetic correlations with risk factors, tissue specificity and colocalisation were examined. RESULTS: Three genome-wide significant loci were identified (rs1491985, rs10490825, rs165599) residing within the genes Ring Finger Protein 123 (RNF123), ATPase secretory pathway Ca (2+) transporting 1 (ATP2C1) and catechol-O-methyltransferase (COMT). The RNF123 locus was replicated (meta-analysis p=0.0002), the ATP2C1 locus showed suggestive association (p=0.0227) and the COMT locus was not replicated. Partial genetic correlation between CWP and depressive symptoms, body mass index, age of first birth and years of schooling were identified. Tissue specificity and colocalisation analysis highlight the relevance of skeletal muscle in CWP. CONCLUSIONS: We report a novel association of RNF123 locus and a suggestive association of ATP2C1 locus with CWP. Both loci are consistent with a role of calcium regulation in CWP. The association with COMT, one of the most studied genes in chronic pain field, was not confirmed in the replication analysis

Acute viral hepatitis morbidity and mortality associated with hepatitis E virus infection: Uzbekistan surveillance data

<p>Abstract</p> <p>Background</p> <p>In Uzbekistan, routine serologic testing has not been available to differentiate etiologies of acute viral hepatitis (AVH). To determine the age groups most affected by hepatitis E virus (HEV) during documented AVH epidemics, trends in AVH-associated mortality rate (MR) per 100,000 over a 15-year period and reported incidence of AVH over a 35-year period were examined.</p> <p>Methods</p> <p>Reported AVH incidence data from 1971 to 2005 and AVH-associated mortality data from 1981 to 1995 were examined. Serologic markers for infection with hepatitis viruses A, B, D, and E were determined from a sample of hospitalized patients with AVH from an epidemic period (1987) and from a sample of pregnant women with AVH from a non-epidemic period (1992).</p> <p>Results</p> <p>Two multi-year AVH outbreaks were identified: one during 1975–1976, and one during 1985–1987. During 1985–1987, AVH-associated MRs were 12.3–17.8 per 100,000 for the general population. Highest AVH-associated MRs occurred among children in the first 3 years of life (40–190 per 100,000) and among women aged 20–29 (15–21 per 100,000). During 1988–1995 when reported AVH morbidity was much lower in the general population, AVH-associated MRs were markedly lower among these same age groups. In 1988, AVH-associated MRs were higher in rural (21 per 100,000) than in urban (8 per 100,000) populations (RR 2.6; 95% CI 1.16–5.93; p < 0.05). Serologic evidence of acute HEV infection was found in 280 of 396 (71%) patients with AVH in 1987 and 12 of 99 (12%) pregnant patients with AVH in 1992.</p> <p>Conclusion</p> <p>In the absence of the availability of confirmatory testing, inferences regarding probable hepatitis epidemic etiologies can sometimes be made using surveillance data, comparing AVH incidence with AVH-associated mortality with an eye to population-based viral hepatitis control measures. Data presented here implicate HEV as the probable etiology of high mortality observed in pregnant women and in children less than 3 years of age in Uzbekistan during 1985–1987. High mortality among pregnant women but not among children less than 3 years has been observed in previous descriptions of epidemic hepatitis E. The high mortality among younger children observed in an AVH outbreak associated with hepatitis E merits corroboration in future outbreaks.</p

Replication of fifteen loci involved in human plasma protein N-glycosylation in 4,802 samples from four cohorts

Human protein glycosylation is a complex process, and its in vivo regulation is poorly understood. Changes in glycosylation patterns are associated with many human diseases and conditions. Understanding the biological determinants of protein glycome provides a basis for future diagnostic and therapeutic applications. Genome-wide association studies (GWAS) allow to study biology via a hypothesis-free search of loci and genetic variants associated with a trait of interest. Sixteen loci were identified by three previous GWAS of human plasma proteome N-glycosylation. However, the possibility that some of these loci are false positives needs to be eliminated by replication studies, which have been limited so far. Here, we use the largest set of samples so far (4,802 individuals) to replicate the previously identified loci. For all but one locus, the expected replication power exceeded 95%. Of the sixteen loci reported previously, fifteen were replicated in our study. For the remaining locus (near the KREMEN1 gene) the replication power was low, and hence replication results were inconclusive. The very high replication rate highlights the general robustness of the GWAS findings as well as the high standards adopted by the community that studies genetic regulation of protein glycosylation. The fifteen replicated loci present a good target for further functional studies. Among these, eight genes encode glycosyltransferases: MGAT5, B3GAT1, FUT8, FUT6, ST6GAL1, B4GALT1, ST3GAL4, and MGAT3. The remaining seven loci offer starting points for further functional follow-up investigation into molecules and mechanisms that regulate human protein N-glycosylation in vivo