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Vitamin D deficiency has been associated with reduced neurocognitive functioning and the neurodegenerative processes. However, existing evidence on brain structural correlates of vitamin D deficiency is controversial. We sought to investigate associations of vitamin D levels with imaging patterns of brain aging. In addition, we investigated whether low vitamin D levels were associated with gray matter volumes, whole brain volumes and hippocampus volumes. Structural MRI data and vitamin D levels were obtained in 1,865 subjects from the general population. Linear regressions were applied to investigate the association of vitamin D levels and vitamin D deficiency with imaging derived brain age, total brain, gray matter and hippocampal volumes. Different sets of covariates were included. Vitamin D deficiency was significantly associated with increased brain age. Also, linear vitamin D levels were significantly associated with total brain and gray matter volumes, while no significant association with hippocampal volume was found. Further interaction analyses showed that this association was only significant for male subjects. Our results support previous findings suggesting that vitamin D-deficient individuals have an accelerated brain aging. In addition, associations between vitamin D levels and total brain/ gray matter volumes suggest neuroprotective effects of vitamin D on the brain., Competing Interests: Declaration of Competing Interests All authors declare no conflicts of interest related to this work., (Copyright © 2022. Published by Elsevier B.V.)

Background: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders., Methods: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors., Results: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged., Conclusions: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders., (Copyright © 2021 Society of Biological Psychiatry. All rights reserved.)

Background: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk., Methods: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH., Results: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10 -8 ), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10 -6 ) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10 -7 ; rs73033497, p = 8.8 × 10 -7 ; rs7914279, p = 6.4 × 10 -7 ), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10 -7 ) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10 -7 ), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10 -7 ) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05)., Conclusions: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels., (Copyright © 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

The discovery of genetic factors for the predisposition of longevity is promising but their functional role and clinical relevance remain largely unclear. Based on results from a large genome-wide association study (GWAS) on human longevity (N ≈ 390,000) we identified six phenotype categories belonging to behavioral and psychiatric traits showing significant genetic correlations using LD Hub. We validated these genetic correlations on the phenotype level in a general population sample using a polygenic risk score (PRS) based on the longevity GWAS as proxy for longevity (N ≈ 8190; Study of Health in Pomerania). The behavioral phenotypes education, smoking and body mass index (BMI) were highly associated with the PRS for longevity especially in females (p education =0.003, p smoking =0.049, p BMI =2.0E-4) with increased rates for higher education, lower smoking rates and decrease in BMI attributed to a higher PRS for longevity. Moreover, the psychiatric phenotypes depression and subjective health complaints showed significant associations (p DEPR =0.032, p SHC =0.002) in females only. Generally, a higher genetic predisposition for longevity had a stronger association with behavioral phenotypes in females than in males. It is unclear what causes the higher ``behavioral heterogeneity'' in males but different biological mechanisms might be involved. Sensitivity analyses showed that the association for the PRS for longevity with BMI and smoking were robust against adjustment with the PRS for BMI and smoking. In conclusion, our analyses demonstrated that genetic information obtained from highly powered GWAS for longevity revealed a clear behavioral signature on the phenotype level in a smaller population based sample., Competing Interests: Conflict of interest HJG has received travel grants and speakers honoraria from Fresenius Medical Care, Neuraxpharm and Janssen Cilag. All other authors declare that they have no conflicts of interest., (Copyright © 2021. Published by Elsevier B.V.)

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 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 × 10 -6 ) and a candidate threshold (1.6 × 10 -4 )., Results: No HLA alleles or C4 haplotypes were associated with depression at the region-wide threshold. HLA-B*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., (Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: The heterogeneity of genetic effects on major depressive disorder (MDD) may be partly attributable to moderation of genetic effects by environment, such as exposure to childhood trauma (CT). Indeed, previous findings in two independent cohorts showed evidence for interaction between polygenic risk scores (PRSs) and CT, albeit in opposing directions. This study aims to meta-analyze MDD-PRS × CT interaction results across these two and other cohorts, while applying more accurate PRSs based on a larger discovery sample., Methods: Data were combined from 3024 MDD cases and 2741 control subjects from nine cohorts contributing to the MDD Working Group of the Psychiatric Genomics Consortium. MDD-PRS were based on a discovery sample of ∼110,000 independent individuals. CT was assessed as exposure to sexual or physical abuse during childhood. In a subset of 1957 cases and 2002 control subjects, a more detailed five-domain measure additionally included emotional abuse, physical neglect, and emotional neglect., Results: MDD was associated with the MDD-PRS (odds ratio [OR] = 1.24, p = 3.6 × 10 -5 , R 2  = 1.18%) and with CT (OR = 2.63, p = 3.5 × 10 -18 and OR = 2.62, p = 1.4 ×10 -5 for the two- and five-domain measures, respectively). No interaction was found between MDD-PRS and the two-domain and five-domain CT measure (OR = 1.00, p = .89 and OR = 1.05, p = .66)., Conclusions: No meta-analytic evidence for interaction between MDD-PRS and CT was found. This suggests that the previously reported interaction effects, although both statistically significant, can best be interpreted as chance findings. Further research is required, but this study suggests that the genetic heterogeneity of MDD is not attributable to genome-wide moderation of genetic effects by CT., (Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: The genetics of depression has been explored in genome-wide association studies that focused on either major depressive disorder or depressive symptoms with mostly negative findings. A broad depression phenotype including both phenotypes has not been tested previously using a genome-wide association approach. We aimed to identify genetic polymorphisms significantly associated with a broad phenotype from depressive symptoms to major depressive disorder., Methods: We analyzed two prior studies of 70,017 participants of European ancestry from general and clinical populations in the discovery stage. We performed a replication meta-analysis of 28,328 participants. Single nucleotide polymorphism (SNP)-based heritability and genetic correlations were calculated using linkage disequilibrium score regression. Discovery and replication analyses were performed using a p-value-based meta-analysis. Lifetime major depressive disorder and depressive symptom scores were used as the outcome measures., Results: The SNP-based heritability of major depressive disorder was 0.21 (SE = 0.02), the SNP-based heritability of depressive symptoms was 0.04 (SE = 0.01), and their genetic correlation was 1.001 (SE = 0.2). We found one genome-wide significant locus related to the broad depression phenotype (rs9825823, chromosome 3: 61,082,153, p = 8.2 × 10 -9 ) located in an intron of the FHIT gene. We replicated this SNP in independent samples (p = .02) and the overall meta-analysis of the discovery and replication cohorts (1.0 × 10 -9 )., Conclusions: This large study identified a new locus for depression. Our results support a continuum between depressive symptoms and major depressive disorder. A phenotypically more inclusive approach may help to achieve the large sample sizes needed to detect susceptibility loci for depression., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Major depressive disorder (MDD) is a disabling mood disorder, and despite a known heritable component, a large meta-analysis of genome-wide association studies revealed no replicable genetic risk variants. Given prior evidence of heterogeneity by age at onset in MDD, we tested whether genome-wide significant risk variants for MDD could be identified in cases subdivided by age at onset., Methods: Discovery case-control genome-wide association studies were performed where cases were stratified using increasing/decreasing age-at-onset cutoffs; significant single nucleotide polymorphisms were tested in nine independent replication samples, giving a total sample of 22,158 cases and 133,749 control subjects for subsetting. Polygenic score analysis was used to examine whether differences in shared genetic risk exists between earlier and adult-onset MDD with commonly comorbid disorders of schizophrenia, bipolar disorder, Alzheimer's disease, and coronary artery disease., Results: We identified one replicated genome-wide significant locus associated with adult-onset (>27 years) MDD (rs7647854, odds ratio: 1.16, 95% confidence interval: 1.11-1.21, p = 5.2 × 10 -11 ). Using polygenic score analyses, we show that earlier-onset MDD is genetically more similar to schizophrenia and bipolar disorder than adult-onset MDD., Conclusions: We demonstrate that using additional phenotype data previously collected by genetic studies to tackle phenotypic heterogeneity in MDD can successfully lead to the discovery of genetic risk factor despite reduced sample size. Furthermore, our results suggest that the genetic susceptibility to MDD differs between adult- and earlier-onset MDD, with earlier-onset cases having a greater genetic overlap with schizophrenia and bipolar disorder., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Schizophrenia has a considerable genetic background. Epidemiological studies suggest an inverse clinical association between schizophrenia and migraine. However, it is unclear to what extent this inverse comorbidity can be explained by genetic mechanisms or by schizophrenia-related behavioral factors. For both disorders hypotheses of glutamate N-methyl-D-aspartate (NMDA) receptor dysfunction have been developed in the past. We hypothesized that both conditions share common genetic factors with inverse effects, primary in the glutamatergic system and genes involved in NMDA activation. Data from the population based Study of Health in Pomerania (N=3973) were used. Based on the results from the recent genome-wide association study for schizophrenia, we calculated polygenic scores (PRS) for subsets of SNPs with different p-value cutoffs and for biological sub-entities. These scores were tested for an association of distinct biological pathways with migraine. The PRS for schizophrenia was inversely associated with migraine in our sample. This association was exclusively based on the genome-wide hits and on single nucleotide polymorphisms near or within genes encoding proteins involved in glutamatergic neurotransmission. This association could be attributed to a single intronic variant rs4523957 in SRR encoding serine-racemase. Additional expression quantitative trait loci analyses of functional variants in SRR and gene-by-gene interaction analyses further supported the validity of this finding. SRR represents the rate limiting enzyme for the synthesis of D-serine, an important co-agonist of the NMDA receptor. According to our results, a decreased versus increased activation of NMDA receptors may play a role in the etiology of schizophrenia, as well as in migraine., (Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.)