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Twin studies are among the most promising strategies for studying heritable disorders, including bipolar disorder (BD). The aim of the present study was to identify distinguishing genes between monozygotic (MZ) twins with different BD phenotype and compare them to their non-affected siblings. Whole-exome sequencing (WES) can identify rare and structural variants that could detect the polygenetic burden of complex disorders. WES was performed on a family composed of two MZ twins with BD, their unaffected brother and unaffected parents. The twins have a discordant response to lithium and distinct course of illness. Following WES, six genes of particular interest emerged: Neurofibromin type 1 (NF1), Biorientation of chromosomes in cell division 1 (BOD1), Golgi-associated gamma adaptin ear-containing ARF binding protein 3 (GGA3), Disrupted in schizophrenia 1 (DISC1), Neuromedin U receptor 2 (NMUR2), and Huntingtin interacting protein 1-related (HIP1R). Interestingly, many of these influence glutamatergic pathways and thus the findings may have therapeutical implications. These results may provide important insights to unveil genetic underpinnings of BD and the response to lithium.

Introduction Bipolar disorder (BD) is a highly heritable and disabling mental illness, commonly associated with substance abuse, being alcohol abuse the most frequent. Comorbid BD and substance abuse disorders are often associated with high levels of health service utilization and destabilization of the course of illness resulting in poor treatment outcomes. Although recent genome-wide association studies have detected a number of risk genes for BD, the data is still sparse and inconclusive for those genes that may contribute to the increased risk of comorbid alcohol abuse (AA) in BD. The primary aim of the present study was to investigate the effects of 46 single-nucleotide polymorphisms (SNPs) within eight genes on different phenotypes of BD patients, such as comorbid alcohol abuse. We further assessed clinical variables associated with AA. Methods One-hundred fifty-eight BD I and II patients were enrolled in a naturalistic cohort study. Genomic DNA of 92 patients was extracted from whole blood using standard procedures and 46 tag SNPs in eight genes of interest (ANK, CACNA1C, CACNB2, FKBP5, GRM7, ITIH3, SYNE1 and TCF4) were genotyped. Results Seventy-one patients out of 158 (45%) satisfied diagnostic criteria for comorbid AA. Among 46 SNPs analyzed, the only SNP associated with comorbid AA was rs1034936 polymorphism in the CANCA1C gene. This polymorphism was also associated with lifetime cocaine abuse, manic switch and current atypical antipsychotics. Conclusions Our findings suggest a role of rs1034936 CACNA1C gene variant in BD-AA group. Despite their preliminary nature, the present results may provide new insight on mechanisms underlying AA in BD.