•A number of genetic variants associated with psychiatric disorders are identified.•Rare variants with large effect sizes are useful for developing disease model.•Integrated model of immune system, ...gut microbiota and genetic risk will be needed.
Recent rapid progress in genome analysis and large-scale consortia has made it possible to discover variants with a variety of allele frequencies and effect sizes associated with psychiatric disorders. Among psychiatric disorder-susceptibility variants, rare variants with large effect sizes detected by sequencing analysis or array comparative genomic hybridization would be particularly useful for elucidating pathophysiology by developing disease models, such as genome-edited mouse or induced pluripotent stem cells. In the last decade, investigations of rare variants with large effect size have revealed an important role of neurodevelopment in the pathogenesis of psychiatric disorders. In future research, integration of recent evidence concerning the contribution of the immune system or gut microbiota will enhance our understanding of psychiatric disorders and facilitate novel drug development.
Schizophrenia is a complex and often chronic psychiatric disorder with high heritability. Diagnosis of schizophrenia is still made clinically based on psychiatric symptoms; no diagnostic tests or ...biomarkers are available. Pathophysiology-based diagnostic scheme and treatments are also not available. Elucidation of the pathogenesis is needed for development of pathology-based diagnostics and treatments. In the past few decades, genetic research has made substantial advances in our understanding of the genetic architecture of schizophrenia. Rare copy number variations (CNVs) and rare single-nucleotide variants (SNVs) detected by whole-genome CNV analysis and whole-genome/-exome sequencing analysis have provided the great advances. Common single-nucleotide polymorphisms (SNPs) detected by large-scale genome-wide association studies have also provided important information. Large-scale genetic studies have been revealed that both rare and common genetic variants play crucial roles in this disorder. In this review, we focused on CNVs, SNVs, and SNPs, and discuss the latest research findings on the pathogenesis of schizophrenia based on these genetic variants. Rare variants with large effect sizes can provide mechanistic hypotheses. CRISPR-based genetics approaches and induced pluripotent stem cell technology can facilitate the functional analysis of these variants detected in patients with schizophrenia. Recent advances in long-read sequence technology are expected to detect variants that cannot be detected by short-read sequence technology. Various studies that bring together data from common variant and transcriptomic datasets provide biological insight. These new approaches will provide additional insight into the pathophysiology of schizophrenia and facilitate the development of pathology-based therapeutics.
We systematically analyzed postzygotic mutations (PZMs) in whole-exome sequences from the largest collection of trios (5,947) with autism spectrum disorder (ASD) available, including 282 unpublished ...trios, and performed resequencing using multiple independent technologies. We identified 7.5% of de novo mutations as PZMs, 83.3% of which were not described in previous studies. Damaging, nonsynonymous PZMs within critical exons of prenatally expressed genes were more common in ASD probands than controls (P < 1 × 10
), and genes carrying these PZMs were enriched for expression in the amygdala (P = 5.4 × 10
). Two genes (KLF16 and MSANTD2) were significantly enriched for PZMs genome-wide, and other PZMs involved genes (SCN2A, HNRNPU and SMARCA4) whose mutation is known to cause ASD or other neurodevelopmental disorders. PZMs constitute a significant proportion of de novo mutations and contribute importantly to ASD risk.
Autism spectrum disorder is a neurodevelopmental disorder present in 1% of the population, characterized by impairments in reciprocal social interaction, communication deficits and restricted ...patterns of behavior. Approximately 10% of the autism spectrum disorder population is thought to have large chromosomal rearrangements. Copy‐number variations (CNV) alter the genome structure either by duplication or deletion of a chromosomal region. The association between CNV and autism susceptibility has become more apparent through the use of methods based on comparative genomic hybridization in screening CNV. The nature of the high CNV rate in the human genome is partly explained by non‐allelic homologous recombination between flanking repeated sequences derived from multiple copies of transposons or mobile genetic elements. There are hotspots for CNV in the human genome, such as 16p11.2 and 22q11.2. Genes involved in CNV are supposed to have copy‐number dose‐dependent effects on the behavior of affected individuals. Animal models give insight into the possible interactions between core genetic loci and additional factors contributing to the phenotypes of each individual. If affected genes code for cellular signaling molecules, reducing the dosage in the intracellular signaling pathway may result in the malfunction of the nervous system. The genetic background of autism spectrum disorder is highly heterogenic and most common or rare CNV do not lead to autism spectrum disorders in the majority of cases, but may occasionally increase the risk of developing an autism spectrum disorder.
Aim
Postnatal depression has demonstrated long‐term consequences on child cognitive and emotional development; however, the link between maternal and child pathology has not been clearly identified. ...We conducted a prospective study using self‐rating questionnaires to clarify the association between bonding disorder and maternal mood during pregnancy and after childbirth.
Methods
A total of 389 women participated in this study and completed questionnaires. Participants were asked to complete the Edinburgh Postnatal Depression Scale (EPDS) and the Mother‐to‐Infant Bonding Scale four times during pregnancy and the postpartum period.
Results
We found statistically significant weak to moderate correlations (r = 0.14–0.39) between the EPDS and Mother‐to‐Infant Bonding Scale scores at each testing period. Women who experienced low mood tended to have stronger bonding disorder. Furthermore, the effectiveness of attachment between the mother and child was closely related to the mood of the mother as measured by the EPDS.
Conclusion
We observed different patterns of bonding and maternal mood. Distinct subtypes regarding maternal mood and formation of mother‐to‐infant attachment suggests that analysis of bonding disorder should be performed considering the course of maternal depressive symptoms.
Genome-wide association studies (GWASs) have identified >100 susceptibility loci for schizophrenia (SCZ) and demonstrated that SCZ is a polygenic disorder determined by numerous genetic variants but ...with small effect size. We conducted a GWAS in the Japanese (JPN) population (a) to detect novel SCZ-susceptibility genes and (b) to examine the shared genetic risk of SCZ across (East Asian EAS and European EUR) populations and/or that of trans-diseases (SCZ, bipolar disorder BD, and major depressive disorder MDD) within EAS and between EAS and EUR (trans-diseases/populations). Among the discovery GWAS subjects (JPN-SCZ GWAS: 1940 SCZ cases and 7408 controls) and replication dataset (4071 SCZ cases and 54479 controls), both comprising JPN populations, 3 novel susceptibility loci for SCZ were identified: SPHKAP (Pbest = 4.1 × 10-10), SLC38A3 (Pbest = 5.7 × 10-10), and CABP1-ACADS (Pbest = 9.8 × 10-9). Subsequent meta-analysis between our samples and those of the Psychiatric GWAS Consortium (PGC; EUR samples) and another study detected 12 additional susceptibility loci. Polygenic risk score (PRS) prediction revealed a shared genetic risk of SCZ across populations (Pbest = 4.0 × 10-11) and between SCZ and BD in the JPN population (P ~ 10-40); however, a lower variance-explained was noted between JPN-SCZ GWAS and PGC-BD or MDD within/across populations. Genetic correlation analysis supported the PRS results; the genetic correlation between JPN-SCZ and PGC-SCZ was ρ = 0.58, whereas a similar/lower correlation was observed between the trans-diseases (JPN-SCZ vs JPN-BD/EAS-MDD, rg = 0.56/0.29) or trans-diseases/populations (JPN-SCZ vs PGC-BD/MDD, ρ = 0.38/0.12). In conclusion, (a) Fifteen novel loci are possible susceptibility genes for SCZ and (b) SCZ "risk" effect is shared with other psychiatric disorders even across populations.
Aim
Eating disorders (EDs) are complex, multifactorial psychiatric conditions. Previous studies identified pathogenic copy number variations associated with NDDs (NDD‐CNVs) in ED patients. However, ...no statistical evidence for an association between NDD‐CNVs and EDs has been demonstrated. Therefore, we examined whether NDD‐CNVs confer risk for EDs.
Methods
Using array comparative genomic hybridization (aCGH), we conducted a high‐resolution CNV analysis of 71 severe female ED patients and 1045 female controls. According to the American College of Medical Genetics guidelines, we identified NDD‐CNVs or pathogenic/likely pathogenic CNVs in NDD‐linked loci. Gene set analysis was performed to examine the involvement of synaptic dysfunction in EDs. Clinical data were retrospectively examined for ED patients with NDD‐CNVs.
Results
Of the samples analyzed with aCGH, 70 severe ED patients (98.6%) and 1036 controls (99.1%) passed our quality control filtering. We obtained 189 and 2539 rare CNVs from patients and controls, respectively. NDD‐CNVs were identified in 10.0% (7/70) of patients and 2.3% (24/1036) of controls. Statistical analysis revealed a significant association between NDD‐CNVs and EDs (odds ratio = 4.69, P = 0.0023). NDD‐CNVs in ED patients included 45,X and deletions at KATNAL2, DIP2A, PTPRT, RBFOX1, CNTN4, MACROD2, and FAM92B. Four of these genes were related to synaptic function. In gene set analysis, we observed a nominally significant enrichment of rare exonic CNVs in synaptic signaling in ED patients (odds ratio = 2.55, P = 0.0254).
Conclusion
Our study provides the first preliminary evidence that NDD‐CNVs may confer risk for severe EDs. The pathophysiology may involve synaptic dysfunction.
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