Yuan-Pang Wang

Revealing the complex genetic architecture of obsessive-compulsive disorder using meta-analysis

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 × 10−7; odds ratio (OR)=1.21; confidence interval (CI): 1.12–1.31, CASC8/CASC11), rs1030757 (P=1.1 × 10−6; OR=1.18; CI: 1.10–1.26, GRID2) and rs12504244 (P=1.6 × 10−6; 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).xa0Strikingly, ∼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.

Atrial fibrillation and the use of oral bisphosphonates

Background: Epidemiological studies investigating a possible association between bisphosphonates and atrial fibrillation (AF) have reported conflicting findings. The objective of our study was to determine whether exposure to oral nitrogen-containing bisphosphonates alendronate and risedronate are associated with increased incidence of atrial fibrillation. Methods: In a retrospective cohort study we analyzed data from three large independent databases, two from the United States (MarketScan® and Ingenix®) and one from the United Kingdom (THIN). 144,548 women, age 50–89, bisphosphonate users during 2002–2005 were compared to 668,891 sex- and age-matched controls (1:4). Our primary outcome measure was new incident atrial fibrillation for up to three years; Cox models adjusted for disease and drug history were used to estimated relative risks. Results: We identified a total of 8,001, 1,984, and 817 AF cases in oral bisphosphonate users and nonusers during 744,340 (MarketScan), 243,898 (Ingenix), and 148,779 (THIN) person-years of follow-up, respectively. Compared to nonusers, overall adjusted relative risk (adjRR) (95% confidence interval [CI]) for AF in oral bisphosphonates users was 0.92 (0.85–0.99; MarketScan), 1.00 (0.87–1.16; Ingenix), and 0.97 (0.79–1.20; THIN); overall adjRR (95% CI) for any cardiac dysrrhythmia for MarketScan was 1.01 (0.98–1.05), Ingenix 1.06 (0.99–1.13), and THIN 0.97 (0.79–1.20). Conclusions: In all three databases from the two countries, the risk of AF or cardiac dysrrhythmia was not increased in postmenopausal women treated for up to three years with oral alendronate or risedronate.

Burden of disease in Brazil, 1990–2016: a systematic subnational analysis for the Global Burden of Disease Study 2016

Summary Background Political, economic, and epidemiological changes in Brazil have affected health and the health system. We used the Global Burden of Disease Study 2016 (GBD 2016) results to understand changing health patterns and inform policy responses. Methods We analysed GBD 2016 estimates for life expectancy at birth (LE), healthy life expectancy (HALE), all-cause and cause-specific mortality, years of life lost (YLLs), years lived with disability (YLDs), disability-adjusted life-years (DALYs), and risk factors for Brazil, its 26 states, and the Federal District from 1990 to 2016, and compared these with national estimates for ten comparator countries. Findings Nationally, LE increased from 68·4 years (95% uncertainty interval [UI] 68·0–68·9) in 1990 to 75·2 years (74·7–75·7) in 2016, and HALE increased from 59·8 years (57·1–62·1) to 65·5 years (62·5–68·0). All-cause age-standardised mortality rates decreased by 34·0% (33·4–34·5), while all-cause age-standardised DALY rates decreased by 30·2% (27·7–32·8); the magnitude of declines varied among states. In 2016, ischaemic heart disease was the leading cause of age-standardised YLLs, followed by interpersonal violence. Low back and neck pain, sense organ diseases, and skin diseases were the main causes of YLDs in 1990 and 2016. Leading risk factors contributing to DALYs in 2016 were alcohol and drug use, high blood pressure, and high body-mass index. Interpretation Health improved from 1990 to 2016, but improvements and disease burden varied between states. An epidemiological transition towards non-communicable diseases and related risks occurred nationally, but later in some states, while interpersonal violence grew as a health concern. Policy makers can use these results to address health disparities. Funding Bill & Melinda Gates Foundation and the Brazilian Ministry of Health.