Primary atopic disorders are a group of inborn errors of immunity that skew the immune system toward severe allergic disease. Defining the biology underlying these extreme monogenic phenotypes... Show morePrimary atopic disorders are a group of inborn errors of immunity that skew the immune system toward severe allergic disease. Defining the biology underlying these extreme monogenic phenotypes reveals shared mechanisms underlying common polygenic allergic disease and identifies potential drug targets. Germline gain-of-function (GOF) variants in JAK1 are a cause of severe atopy and eosinophilia. Modeling the JAK1GOF (p.A634D) variant in both zebrafish and human induced pluripotent stem cells (iPSCs) revealed enhanced myelopoiesis. RNA-Seq of JAK1GOF human whole blood, iPSCs, and transgenic zebrafish revealed a shared core set of dysregulated genes involved in IL-4, IL-13, and IFN signaling. Immunophenotypic and transcriptomic analysis of patients carrying a JAK1GOF variant revealed marked Th cell skewing. Moreover, long-term ruxolitinib treatment of 2 children carrying the JAK1GOF (p.A634D) variant remarkably improved their growth, eosinophilia, and clinical features of allergic inflammation. This work highlights the role of JAK1 signaling in atopic immune dysregulation and the clinical impact of JAK1/2 inhibition in treating eosinophilic and allergic disease. Show less
Community resilience entails the community’s ongoing and developing capacity to account for its vulnerabilities and function amid and recover from disturbance. A holistic and systematic approach of... Show moreCommunity resilience entails the community’s ongoing and developing capacity to account for its vulnerabilities and function amid and recover from disturbance. A holistic and systematic approach of the community on how it uses material and energy resources or how a society educates the members’ over time is required to learn from the past and adapt to the present and future opportunities and threads. Community resilience has a long history in the local communities, which is embedded in their culture and history around shared values and local knowledge based on a dedicated and robust collaboration among diverse groups of the community and the various actors from different backgrounds. The innovative partnership between various actors such as stakeholders, research entities, local communities, and third sector parties is required to overcome the complexities of resiliency building. Using local knowledge to understand the local needs better is crucial in developing local, sustainable solutions and building community resilience over time. Show less
BACKGROUND: The prevalence of depression is higher in individuals with autoimmune diseases, but the mechanisms underlying the observed comorbidities are unknown. Shared genetic etiology is a... Show moreBACKGROUND: The prevalence of depression is higher in individuals with autoimmune diseases, but the mechanisms underlying the observed comorbidities are unknown. Shared genetic etiology is a plausible explanation for the overlap, and in this study we tested whether genetic variation in the major histocompatibility complex (MHC), which is associated with risk for autoimmune diseases, is also associated with risk for depression.METHODS: We fine-mapped the classical MHC (chr6: 29.6-33.1 Mb), imputing 216 human leukocyte antigen (HLA) alleles and 4 complement component 4 (C4) haplotypes in studies from the Psychiatric Genomics Consortium Major Depressive Disorder Working Group and the UK Biobank. The total sample size was 45,149 depression cases and 86,698 controls. We tested for association between depression status and imputed MHC variants, applying both a region-wide significance threshold (3.9 x 10(-6) ) and a candidate threshold (1.6 x 10(-4) ).RESULTS: No HLA alleles or C4 haplotypes were associated with depression at the region-wide threshold. HLAB*08:01 was associated with modest protection for depression at the candidate threshold for testing in HLA genes in the meta-analysis (odds ratio = 0.98, 95% confidence interval = 0.97-0.99).CONCLUSIONS: We found no evidence that an increased risk for depression was conferred by HLA alleles, which play a major role in the genetic susceptibility to autoimmune diseases, or C4 haplotypes, which are strongly associated with schizophrenia. These results suggest that any HLA or C4 variants associated with depression either are rare or have very modest effect sizes. Show less
Depression is more frequent among individuals exposed to traumatic events. Both trauma exposure and depression are heritable. However, the relationship between these traits, including the role of... Show moreDepression is more frequent among individuals exposed to traumatic events. Both trauma exposure and depression are heritable. However, the relationship between these traits, including the role of genetic risk factors, is complex and poorly understood. When modelling trauma exposure as an environmental influence on depression, both gene-environment correlations and gene-environment interactions have been observed. The UK Biobank concurrently assessed Major Depressive Disorder (MDD) and self-reported lifetime exposure to traumatic events in 126,522 genotyped individuals of European ancestry. We contrasted genetic influences on MDD stratified by reported trauma exposure (final sample size range: 24,094-92,957). The SNP-based heritability of MDD with reported trauma exposure (24%) was greater than MDD without reported trauma exposure (12%). Simulations showed that this is not confounded by the strong, positive genetic correlation observed between MDD and reported trauma exposure. We also observed that the genetic correlation between MDD and waist circumference was only significant in individuals reporting trauma exposure (r(g) = 0.24, p = 1.8 x 10(-7) versus r(g) = -0.05, p = 0.39 in individuals not reporting trauma exposure, difference p = 2.3 x 10(-4)). Our results suggest that the genetic contribution to MDD is greater when reported trauma is present, and that a complex relationship exists between reported trauma exposure, body composition, and MDD. Show less
Choi, K.W.; Chen, C.Y.; Stein, M.B.; Klimentidis, Y.C.; Wang, M.J.; Koenen, K.C.; ... ; Major Depressive Disorder Working 2019
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... Show moreIMPORTANCE 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. Show less
Grove, J.; Ripke, S.; Als, T.D.; Mattheisen, M.; Walters, R.K.; Won, H.; ... ; 23andMe Re 2019
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... Show moreAutism 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. Show less
Stress is associated with poorer physical and mental health. To improve our understanding of this link, we performed genome-wide association studies (GWAS) of depressive symptoms and genome-wide by... Show moreStress is associated with poorer physical and mental health. To improve our understanding of this link, we performed genome-wide association studies (GWAS) of depressive symptoms and genome-wide by environment interaction studies (GWEIS) of depressive symptoms and stressful life events (SLE) in two UK population-based cohorts (Generation Scotland and UK Biobank). No SNP was individually significant in either GWAS, but gene-based tests identified six genes associated with depressive symptoms in UK Biobank (DCC, ACSS3, DRD2, STAG1, FOXP2 and KYNU; p < 2.77 x 10(-6)). Two SNPs with genome-wide significant GxE effects were identified by GWEIS in Generation Scotland: rs12789145 (53-kb downstream PIWIL4; p = 4.95 x 10(-9); total SLE) and rs17070072 (intronic to ZCCHC2; p = 1.46 x 10(-8); dependent SLE). A third locus upstream CYLC2 (rs12000047 and rs12005200, p < 2.00 x 10(-8); dependent SLE) when the joint effect of the SNP main and GxE effects was considered. GWEIS gene-based tests identified: MTNR1B with GxE effect with dependent SLE in Generation Scotland; and PHF2 with the joint effect in UK Biobank (p < 2.77 x 10(-6)). Polygenic risk scores (PRSs) analyses incorporating GxE effects improved the prediction of depressive symptom scores, when using weights derived from either the UK Biobank GWAS of depressive symptoms (p = 0.01) or the PGC GWAS of major depressive disorder (p = 5.91 x 10(-3)). Using an independent sample, PRS derived using GWEIS GxE effects provided evidence of shared aetiologies between depressive symptoms and schizotypal personality, heart disease and COPD. Further such studies are required and may result in improved treatments for depression and other stress-related conditions. Show less
AbstractElectroconvulsive therapy (ECT) is the treatment of choice for severe and treatment-resistantdepression; disorder severity and unfavorable treatment outcomes are shown to be influencedby an... Show moreAbstractElectroconvulsive therapy (ECT) is the treatment of choice for severe and treatment-resistantdepression; disorder severity and unfavorable treatment outcomes are shown to be influencedby an increased genetic burden for major depression (MD). Here, we tested whether ECT assign-ment and response/nonresponse are associated with an increased genetic burden for majordepression (MD) using polygenic risk score (PRS), which summarize the contribution of disease-related common risk variants. Fifty-one psychiatric inpatients suffering from a major depressiveepisode underwent ECT. MD-PRS were calculated for these inpatients and a separatepopulation-based sample (n = 3,547 healthy; n = 426 self-reported depression) based on sum-mary 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 statusbetween ECT patients and healthy controls (p = .022, R2 = 1.173%); patients showed higherMD-PRS. MD-PRS in population-based depression self-reporters were intermediate betweenECT 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 indi-cate that ECT cohorts show an increased genetic burden for MD and are consistent with thehypothesis that treatment-resistant MD patients represent a subgroup with an increased geneticrisk for MD. Larger samples are needed to better substantiate these findings. Show less
Wray, N.R.; Ripke, S.; Mattheisen, M.; Trzaskowski, M.; Byrne, E.M.; Abdellaoui, A.; ... ; Major Depressive Disorder Working 2018