21 research outputs found
Identification of common genetic risk variants for autism spectrum disorder
Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD
Evidence for Increased Genetic Risk Load for Major Depression in Patients Assigned to Electroconvulsive Therapy
Electroconvulsive therapy (ECT) is the treatment of choice for severe and treatment-resistant
depression; disorder severity and unfavorable treatment outcomes are shown to be influenced
by an increased genetic burden for major depression (MD). Here, we tested whether ECT assignment
and response/nonresponse are associated with an increased genetic burden for major
depression (MD) using polygenic risk score (PRS), which summarize the contribution of diseaserelated
common risk variants. Fifty-one psychiatric inpatients suffering from a major depressive
episode underwent ECT. MD-PRS were calculated for these inpatients and a separate
population-based sample (n = 3,547 healthy; n = 426 self-reported depression) based on summary
statistics from the Psychiatric Genomics Consortium MDD-working group (Cases:
n = 59,851; Controls: n = 113,154). MD-PRS explained a significant proportion of disease status
between ECT patients and healthy controls (p = .022, R2 = 1.173%); patients showed higher
MD-PRS. MD-PRS in population-based depression self-reporters were intermediate between
ECT patients and controls (n.s.). Significant associations between MD-PRS and ECT response
(50% reduction in Hamilton depression rating scale scores) were not observed. Our findings indicate
that ECT cohorts show an increased genetic burden for MD and are consistent with the
hypothesis that treatment-resistant MD patients represent a subgroup with an increased genetic
risk for MD. Larger samples are needed to better substantiate these findings
The origin of the isolated population of the Faroe Islands investigated using Y chromosomal markers
Historical, archaeological and linguistic sources suggest that the ancestors of the present day population in the Faroe Islands may have their origin in several different regions surrounding the North Atlantic Ocean. In this study we use binary and microsatellite markers of the Y chromosome to analyse genetic diversity in the Faroese population and to compare this with the distribution of genotypes in the putative ancestral populations. Using a combination of genetic distance measures, assignment and phylogenetic analyses, we find a high degree of similarity between the Faroese Y chromosomes and the Norwegian, Swedish and Icelandic Y chromosomes but also some similarity with the Scottish and Irish Y chromosomes. Diversity measures and estimates of effective population sizes also suggest that the original gene pool of the settlers have been influenced by random genetic drift, thus complicating direct comparisons with other populations. No extensive immigration from Iceland to the Faroe Islands can be documented in the historical record. We therefore hypothesise that the high degree of Y chromosome similarity between the two populations arose because they were colonised at approximately the same time by males originating from the same regions of Scandinavia and, to a lesser extent, from the British Isles
Erratum: DIRAS2 is associated with adult ADHD, related traits, and co-morbid disorders (Neuropsychopharmacology (2011) 36 (2318-2327) DOI: 10.1038/npp.2011.120)
Assessment of bidirectional relationships between physical activity and depression among adults A 2-Sample mendelian randomization study
IMPORTANCE Increasing evidence shows that physical activity is associated with reduced risk for depression, pointing to a potential modifiable target for prevention. However, the causality and direction of this association are not clear; physical activity may protect against depression, and/or depression may result in decreased physical activity.OBJECTIVE To examine bidirectional relationships between physical activity and depression using a genetically informed method for assessing potential causal inference.DESIGN, SETTING, AND PARTICIPANTS This 2-sample mendelian randomization (MR) used independent top genetic variants associated with 2 physical activity phenotypes-self- reported (n = 377 234) and objective accelerometer-based (n = 91 084)-and with major depressive disorder (MDD) (n = 143 265) as genetic instruments from the largest available, nonoverlapping genome-wide association studies (GWAS). GWAS were previously conducted in diverse observational cohorts, including the UK Biobank (for physical activity) and participating studies in the Psychiatric Genomics Consortium (for MDD) among adults of European ancestry. Mendelian randomization estimates from each genetic instrument were combined using inverse variance weighted meta-analysis, with alternate methods (eg, weighted median, MR Egger, MR-Pleiotropy Residual Sum and Outlier [PRESSO]) and multiple sensitivity analyses to assess horizontal pleiotropy and remove outliers. Data were analyzed from May 10 through July 31, 2018.MAIN OUTCOMES AND MEASURES MDD and physical activity.RESULTS GWAS summary data were available for a combined sample size of 611 583 adult participants. Mendelian randomization evidence suggested a protective relationship between accelerometer-based activity and MDD (odds ratio [ OR], 0.74 for MDD per 1-SD increase in mean acceleration; 95% CI, 0.59-0.92; P = .006). In contrast, there was no statistically significant relationship between MDD and accelerometer-based activity (beta = -0.08 in mean acceleration per MDD vs control status; 95% CI, -0.47 to 0.32; P = .70). Furthermore, there was no significant relationship between self-reported activity and MDD (OR, 1.28 for MDD per 1-SD increase in metabolic-equivalent minutes of reported moderate-to-vigorous activity; 95% CI, 0.57-3.37; P = .48), or between MDD and self-reported activity (beta = 0.02 per MDD in standardized metabolic-equivalent minutes of reported moderate-to-vigorous activity per MDD vs control status; 95% CI, -0.008 to 0.05; P = .15).CONCLUSIONS AND RELEVANCE Using genetic instruments identified from large-scale GWAS, robust evidence supports a protective relationship between objectively assessed-but not self-reported-physical activity and the risk for MDD. Findings point to the importance of objective measurement of physical activity in epidemiologic studies of mental health and support the hypothesis that enhancing physical activity may be an effective prevention strategy for depression
Genetic Association of Major Depression With Atypical Features and Obesity-Related Immunometabolic Dysregulations
DIRAS2 is associated with adult ADHD, related traits, and co-morbid disorders
Several linkage analyses implicated the chromosome 9q22 region in attention deficit/hyperactivity disorder (ADHD), a neurodevelopmental disease with remarkable persistence into adulthood. This locus contains the brain-expressed GTP-binding RAS-like 2 gene (DIRAS2) thought to regulate neurogenesis. As DIRAS2 is a positional and functional ADHD candidate gene, we conducted an association study in 600 patients suffering from adult ADHD (aADHD) and 420 controls. Replication samples consisted of 1035 aADHD patients and 1381 controls, as well as 166 families with a child affected from childhood ADHD. Given the high degree of co-morbidity with ADHD, we also investigated patients suffering from bipolar disorder (BD) (n=336) or personality disorders (PDs) (n=622). Twelve single-nucleotide polymorphisms (SNPs) covering the structural gene and the transcriptional control region of DIRAS2 were analyzed. Four SNPs and two haplotype blocks showed evidence of association with ADHD, with nominal p-values ranging from p=0.006 to p=0.05. In the adult replication samples, we obtained a consistent effect of rs1412005 and of a risk haplotype containing the promoter region (p=0.026). Meta-analysis resulted in a significant common OR of 1.12 (p=0.04) for rs1412005 and confirmed association with the promoter risk haplotype (OR=1.45, p=0.0003). Subsequent analysis in nuclear families with childhood ADHD again showed an association of the promoter haplotype block (p=0.02). rs1412005 also increased risk toward BD (p=0.026) and cluster B PD (p=0.031). Additional SNPs showed association with personality scores (p=0.008-0.048). Converging lines of evidence implicate genetic variance in the promoter region of DIRAS2 in the etiology of ADHD and co-morbid impulsive disorders