An Emerging Natural History in the Development, Mechanisms and Worldwide Prevalence of Major Mental Disorders

Conciliating recent findings from molecular genetics, evolutionary biology, and clinical observations together point to new understandings regarding the mechanism, development and the persistent worldwide prevalence of major mental disorders (MMDs), which should be considered the result of an evolutionary downside trade off. Temperamental/trait variability, by facilitating choices for individual and group responses, confers robustness flexibility and resilience crucial to success of our species. Extreme temperamental variants, originating evolutionarily from the asocial aspect of human nature, also constitute the premorbid personality of the disorders. The latter create vulnerable individuals out of whom some will develop MMDs but at much higher rate to that of the general population. Significantly, similar temperamental “lopsidedness� enables many of these vulnerable individuals, if intelligent, tenacious, and curious, to be creative and contribute to our survival while some may also develop MMDs. All have a common neural-developmental origin and share characteristics in their clinical expression and pharmacological responses also expressed as mixed syndromes or alternating ones over time. Over-pruning of synaptic neurons may be considered the trigger of such occurrences or conversely, the failure to prevent them in spite of it. The symptoms of the major mental disorders are made up of antithetical substitutes as an expression of a disturbed over-all synchronizing property of brain function for all higher faculties previously unconsidered in their modeling. The concomitant presence of psychosis is a generic common occurrence

Genome-wide Burden of Rare Short Deletions is Enriched in Major Depressive Disorder in Four Cohorts

Major depressive disorder (MDD) is moderately heritable, with a high prevalence and a presumed high heterogeneity. Copy number variants (CNVs) could contribute to the heritable component of risk, but the two previous genome-wide association studies of rare CNVs did not report significant findings. In this meta-analysis of four cohorts (5780 patients and 6626 control subjects), we analyzed the association of MDD to 1) genome-wide burden of rare deletions and duplications, partitioned by length (100 kb) and other characteristics, and 2) individual rare exonic CNVs and CNV regions. Patients with MDD carried significantly more short deletions than control subjects (p = .0059) but not long deletions or short or long duplications. The confidence interval for long deletions overlapped with that for short deletions, but long deletions were 70% less frequent genome-wide, reducing the power to detect increased burden. The increased burden of short deletions was primarily in intergenic regions. Short deletions in cases were also modestly enriched for high-confidence enhancer regions. No individual CNV achieved thresholds for suggestive or significant association after genome-wide correction. p values < .01 were observed for 15q11.2 duplications (TUBGCP5, CYFIP1, NIPA1, and NIPA2), deletions in or near PRKN or MSR1, and exonic duplications of ATG5. The increased burden of short deletions in patients with MDD suggests that rare CNVs increase the risk of MDD by disrupting regulatory regions. Results for longer deletions were less clear, but no large effects were observed for long multigenic CNVs (as seen in schizophrenia and autism). Further studies with larger sample sizes are warranted. [Abstract copyright: Copyright © 2019 Society of Biological Psychiatry. All rights reserved.

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

The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape : A Large-Scale Genome-Wide Interaction Study

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age-and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to similar to 2.8M SNPs with BMI and WHRadjBMI in four strata (men 50y, women 50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR= 50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may providefurther insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.Peer reviewe

The genetic relevance of human iPSC-derived microglia to Alzheimer’s disease and major neuropsychiatric disorders

Microglia are the primary innate immune cell type in the brain that have been implicated in the pathogenesis of several neurodegenerative and neuropsychiatric disorders, most notably Alzheimer’s disease (AD) and schizophrenia. Microglia generated from human induced pluripotent stem cells (hiPSCs) represent a promising in vitro cellular model for studying the neuroimmune interactions involved in these disorders. Among several methods of generating ­hiPSC-derived microglia (iMG) – varying in duration and resultant purity – a recent protocol by Brownjohn et al. [Stem Cell Reports. 2018 Apr;10(4):1294–307] is particularly simple and efficient. However, the replicability of this method, transcriptomic similarity of these iMG to primary adult microglia, and their genetic relevance to disease (i.e., enrichment of disease risk loci in genes preferentially expressed in these cells) remains unclear. Using two hiPSC lines, we demonstrated that Brownjohn’s protocol can rapidly generate iMG that morphologically and functionally resembled microglia. The iMG cells we generated were found to be transcriptionally similar to previously reported iMG, as well as fetal and adult microglia. Furthermore, by using cell type-specific gene expression to partition disease heritability, we showed that iMG cells are genetically relevant to AD but found no significant enrichments of risk loci of Parkinson’s disease, schizophrenia, major depressive disorder, bipolar disorder, autism spectrum disorder, or body mass index. Across a range of neuronal and immune cell types, we found only iMG, primary microglia, and microglia-like cell types exhibited a significant enrichment for AD heritability. Our results thus support the use of iMG as a human cellular model for understanding AD biology and underlying genetic factors, as well as for developing and efficiently screening new therapeutics

Polygenic Dissection of Diagnosis and Clinical Dimensions of Bipolar Disorder and Schizophrenia

Bipolar disorder and schizophrenia are two often severe disorders with high heritabilities. Recent studies have demonstrated a large overlap of genetic risk loci between these disorders but diagnostic and molecular distinctions still remain. Here, we perform a combined genome-wide association study (GWAS) of 19 779 bipolar disorder (BP) and schizophrenia (SCZ) cases versus 19 423 controls, in addition to a direct comparison GWAS of 7129 SCZ cases versus 9252 BP cases. In our case–control analysis, we identify five previously identified regions reaching genome-wide significance (CACNA1C, IFI44L, MHC, TRANK1 and MAD1L1) and a novel locus near PIK3C2A. We create a polygenic risk score that is significantly different between BP and SCZ and show a significant correlation between a BP polygenic risk score and the clinical dimension of mania in SCZ patients. Our results indicate that first, combining diseases with similar genetic risk profiles improves power to detect shared risk loci and second, that future direct comparisons of BP and SCZ are likely to identify loci with significant differential effects. Identifying these loci should aid in the fundamental understanding of how these diseases differ biologically. These findings also indicate that combining clinical symptom dimensions and polygenic signatures could provide additional information that may someday be used clinically