Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes

Type 2 diabetes (T2D) is a very common disease in humans. Here we conduct a meta-analysis of genome-wide association studies (GWAS) with ~16 million genetic variants in 62,892 T2D cases and 596,424 controls of European ancestry. We identify 139 common and 4 rare variants associated with T2D, 42 of which (39 common and 3 rare variants) are independent of the known variants. Integration of the gene expression data from blood (n = 14,115 and 2765) with the GWAS results identifies 33 putative functional genes for T2D, 3 of which were targeted by approved drugs. A further integration of DNA methylation (n = 1980) and epigenomic annotation data highlight 3 genes (CAMK1D, TP53INP1, and ATP5G1) with plausible regulatory mechanisms, whereby a genetic variant exerts an effect on T2D through epigenetic regulation of gene expression. Our study uncovers additional loci, proposes putative genetic regulatory mechanisms for T2D, and provides evidence of purifying selection for T2D-associated variants

Age at first birth in women is genetically associated with increased risk of schizophrenia

Prof. Paunio on PGC:n jäsenPrevious studies have shown an increased risk for mental health problems in children born to both younger and older parents compared to children of average-aged parents. We previously used a novel design to reveal a latent mechanism of genetic association between schizophrenia and age at first birth in women (AFB). Here, we use independent data from the UK Biobank (N = 38,892) to replicate the finding of an association between predicted genetic risk of schizophrenia and AFB in women, and to estimate the genetic correlation between schizophrenia and AFB in women stratified into younger and older groups. We find evidence for an association between predicted genetic risk of schizophrenia and AFB in women (P-value = 1.12E-05), and we show genetic heterogeneity between younger and older AFB groups (P-value = 3.45E-03). The genetic correlation between schizophrenia and AFB in the younger AFB group is -0.16 (SE = 0.04) while that between schizophrenia and AFB in the older AFB group is 0.14 (SE = 0.08). Our results suggest that early, and perhaps also late, age at first birth in women is associated with increased genetic risk for schizophrenia in the UK Biobank sample. These findings contribute new insights into factors contributing to the complex bio-social risk architecture underpinning the association between parental age and offspring mental health.Peer reviewe

Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa

Anorexia nervosa (AN) is a complex neuropsychiatric disorder presenting with dangerously low body weight, and a deep and persistent fear of gaining weight. To date, only one genome-wide significant locus associated with AN has been identified. We performed an exome-chip based genome-wide association studies (GWAS) in 2158 cases from nine populations of European origin and 15 485 ancestrally matched controls. Unlike previous studies, this GWAS also probed association in low-frequency and rare variants. Sixteen independent variants were taken forward for in silico and de novo replication (11 common and 5 rare). No findings reached genome-wide significance. Two notable common variants were identified: rs10791286, an intronic variant in OPCML (P=9.89 × 10 -6), and rs7700147, an intergenic variant (P=2.93 × 10 -5). No low-frequency variant associations were identified at genome-wide significance, although the study was well-powered to detect low-frequency variants with large effect sizes, suggesting that there may be no AN loci in this genomic search space with large effect sizes

Integrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns

Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. Here we examine the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs) in 4 independent cohorts (overall n = 2365). We use Akaike’s information criterion to test which factors best explain variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E), genotypes in cis (G), or their additive (G + E) or interaction (GxE) effects. Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G + E or GxE are functionally distinct. The enrichment of genetic variants from GxE models in GWAS for complex disorders supports their importance for disease risk

Identifying gene targets for brain-related traits using transcriptomic and methylomic data from blood

Understanding the difference in genetic regulation of gene expression between brain and blood is important for discovering genes for brain-related traits and disorders. Here, we estimate the correlation of genetic effects at the top-associated cis-expression or -DNA methylation (DNAm) quantitative trait loci (cis-eQTLs or cis-mQTLs) between brain and blood (r b ). Using publicly available data, we find that genetic effects at the top cis-eQTLs or mQTLs are highly correlated between independent brain and blood samples (r b = 0.70 for cis-eQTLs and r ^ b = 0.78 for cis-mQTLs). Using meta-analyzed brain cis-eQTL/mQTL data (n = 526 to 1194), we identify 61 genes and 167 DNAm sites associated with four brain-related phenotypes, most of which are a subset of the discoveries (97 genes and 295 DNAm sites) using data from blood with larger sample sizes (n = 1980 to 14,115). Our results demonstrate the gain of power in gene discovery for brain-related phenotypes using blood cis-eQTL/mQTL data with large sample sizes. © 2018 The Author(s).Peer reviewe

Enhancing Psychosis-Spectrum Nosology Through an International Data Sharing Initiative.

The latent structure of schizotypy and psychosis-spectrum symptoms remains poorly understood. Furthermore, molecular genetic substrates are poorly defined, largely due to the substantial resources required to collect rich phenotypic data across diverse populations. Sample sizes of phenotypic studies are often insufficient for advanced structural equation modeling approaches. In the last 50 years, efforts in both psychiatry and psychological science have moved toward (1) a dimensional model of psychopathology (eg, the current Hierarchical Taxonomy of Psychopathology [HiTOP] initiative), (2) an integration of methods and measures across traits and units of analysis (eg, the RDoC initiative), and (3) powerful, impactful study designs maximizing sample size to detect subtle genomic variation relating to complex traits (the Psychiatric Genomics Consortium [PGC]). These movements are important to the future study of the psychosis spectrum, and to resolving heterogeneity with respect to instrument and population. The International Consortium of Schizotypy Research is composed of over 40 laboratories in 12 countries, and to date, members have compiled a body of schizotypy- and psychosis-related phenotype data from more than 30000 individuals. It has become apparent that compiling data into a protected, relational database and crowdsourcing analytic and data science expertise will result in significant enhancement of current research on the structure and biological substrates of the psychosis spectrum. The authors present a data-sharing infrastructure similar to that of the PGC, and a resource-sharing infrastructure similar to that of HiTOP. This report details the rationale and benefits of the phenotypic data collective and presents an open invitation for participation

Correction: Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa

The fortieth author's name was listed incorrectly. The correct presentation is A Keski-Rahkonen

Quantifying prion disease penetrance using large population control cohorts

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Kinematic Evidence For Top-quark Pair Production In W Plus Multijet Events In P(p)over-bar Collisions At Root-s=1.8 Tev

We present a study of W+multijet events that compares the kinematics of the observed events with expectations from direct QCD W+jet production and from production and decay of top quark pairs. The data were collected in the 1992-93 run with the Collider Detector at Fermilab (CDF) from 19.3 pb-1 of proton-antiproton collisions at s =1.8 TeV. A W+2 jet sample and a W+3 jet sample are selected with the requirement that at least the two or three jets have energy transverse with respect to the beam axis in excess of 20 GeV. The jet energy distributions for the W+2 jet sample agree well with the predictions of direct QCD W production. From the W+3 jet events, a "signal sample" with an improved ratio of tt̄ to QCD produced W events is selected by requiring each jet to be emitted centrally in the event center of mass frame. This sample contains 14 events with unusually hard jet ET distributions not well described by expectations for jets from direct QCD W production and other background processes. Using expected jet ET distributions, a relative likelihood is defined and used to determine if an event is more consistent with the decay of tt̄ pairs, with Mtop=170 GeV/c2, than with direct QCD W production. Eight of the 14 signal sample events are found to be more consistent with top-quark than direct QCD W production, while only 1.7 such top-quark-like events are expected in the absence of tt̄. The probability that the observation is due to an upward fluctuation of the number of background events is found to be 0.8%. The robustness of the result was tested by varying the cuts defining the signal sample, and the largest probability for such a fluctuation found was 1.9%. Good agreement in the jet spectra is obtained if jet production from tt̄ pair decays is included. For those events kinematically more consistent with tt̄ we find evidence for a b-quark content in their jets to the extent expected from top quark decay, and larger than expected for background processes. For events with four or more jets, the discrepancy with the predicted jet distributions from direct QCD W production, and the associated excess of b-quark content, is more pronounced. © 1995 The American Physical Societ

Branching fraction and CP asymmetries of B0→KS0KS0KS0

We present measurements of the branching fraction and time-dependent CP-violating asymmetries in B0→K0SK0SK0S decays based on 227×106 Υ(4S)→BB decays collected with the BABAR detector at the PEP-II asymmetric-energy B factory at SLAC. We obtain a branching fraction of (6.9+0.9−0.8±0.6)×10−6, and CP asymmetries C=−0.34+0.28−0.25±0.05 and S=−0.71+0.38−0.32±0.04, where the first uncertainties are statistical and the second systematic