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Aim Rare missense variants, which likely account for a substantial portion of the genetic ‘dark matter’ for a common complex disease, are challenging because the impacts of variants on disease development are difficult to substantiate. This study aimed to examine the impacts of amino acid substitution variants in the POLG1 found in bipolar disorder, as an example and proof of concept, in three different modalities of assessment: in silico predictions, in vitro biochemical assays, and clinical evaluation. We then tested whether deleterious variants in POLG1 contributed to the genetics of bipolar disorder. Methods We searched for variants in the POLG1 gene in 796 Japanese patients with bipolar disorder and 767 controls and comprehensively investigated all 23 identified variants in the three modalities of assessment. POLG1 encodes mitochondrial DNA polymerase and is one of the causative genes for a Mendelian-inheritance mitochondrial disease, which is occasionally accompanied by mood disorders. The healthy control data from the Tohoku Medical Megabank Organization were also employed. Results Although the frequency of carriers of deleterious variants varied from one method to another, every assessment achieved the same conclusion that deleterious POLG1 variants were significantly enriched in the variants identified in patients with bipolar disorder compared to those in controls. Conclusion Together with mitochondrial dysfunction in bipolar disorder, the present results suggested deleterious POLG1 variants as a credible risk for the multifactorial disease.

Owing to recent advances in DNA sequencing technology, a number of large-scale comprehensive analyses of genetic variations in protein-coding regions (i.e., whole-exome sequencing studies), have been conducted for neuropsychiatric and neurodevelopmental disorders, such as autism spectrum disorders, intellectual disability, and schizophrenia. These studies, especially those focusing on de novo (newly arising) mutations and extremely rare variants, have successfully identified previously unrecognized disease genes/mutations with a large effect size and deepen our understanding of the biology of neuropsychiatric diseases. Along with the continuously dropping sequencing cost, now the target of sequencing studies is expanding from the exome to the whole human genome. Several pioneering works have provided important insights into the contribution of rare non-coding variants to neuropsychiatric diseases. At the same time, these studies highlight need for further larger sample sizes and improvement in annotation of non-coding regulatory variants. In this review, key findings from recent studies as well as likely future directions are overviewed.

Aim: Recent genome-wide association studies (GWAS) of bipolar disorder (BD) have detected new candidate genes, including DGKH, DFNB31 and SORCS2. However, the results of these GWAS were not necessarily consistent, indicating the importance of replication studies. In this study, we tested the genetic association of DGKH, DFNB31 and SORCS2 with BD. Methods: We genotyped 18 single-nucleotide polymorphisms (SNP) in DGKH, DFNB31 and SORCS2 using Japanese samples (366 cases and 370 controls). We also performed a meta-analysis of four SNP in DGKH, using the previously published allele frequency data of Han-Chinese case–control samples (1139 cases and 1138 controls). Results: In the association analysis using Japanese samples, a SNP in SORCS2 (rs10937823) showed nominal genotypic association. However, we could not find any association in an additional analysis of tag SNP around rs10937823. In the meta-analysis of SNP in DGKH, rs9315897, which was not significantly associated with BD in the previous Chinese study, showed nominal association. Conclusion: Although the association was not strong, the result of this study would support the association between DGKH and BD.

Recent genome-wide association studies (GWAS) of bipolar disorder (BD) have detected new candidate genes, including DGKH, DFNB31 and SORCS2. However, the results of these GWAS were not necessarily consistent, indicating the importance of replication studies. In this study, we tested the genetic association of DGKH, DFNB31 and SORCS2 with BD.We genotyped 18 single-nucleotide polymorphisms (SNP) in DGKH, DFNB31 and SORCS2 using Japanese samples (366 cases and 370 controls). We also performed a meta-analysis of four SNP in DGKH, using the previously published allele frequency data of Han-Chinese case-control samples (1139 cases and 1138 controls).IN the association analysis using Japanese samples, a SNP in SORCS2 (rs10937823) showed nominal genotypic association. However, we could not find any association in an additional analysis of tag SNP around rs10937823. In the meta-analysis of SNP in DGKH, rs9315897, which was not significantly associated with BD in the previous Chinese study, showed nominal association.Although the association was not strong, the result of this study would support the association between DGKH and BD.