A commentary on the gender-specific association of TSNAX/DISC1 locus for schizophrenia and bipolar affective disorder in South Indian population

The disrupted-in-schizophrenia-1 (DISC1) gene was originally identified from the breakpoint of a chromosomal translocation (1;11) (q42.1;q14.3) in a large Scottish family with major mental disorders, including schizophrenia (SCZ), bipolar affective disorder (BPAD) and recurrent major depression.^{1, 2} Subsequently, many genetic evidences for the involvement of DISC1 in SCZ have been reported in different populations,³ and DISC1 has become one of the putative susceptibility genes for SCZ. In this issue, Ram Murthy et al.⁴ reported a gender-specific DISC1 contribution in SCZ, BPAD and combined samples in South Indian population.

The first concern is the risk alleles and the haplotypes identified. Although the results of genetic replication studies between SCZ and the DISC1 gene must be interpreted with extreme caution,⁵ a critical issue in positive DISC1 association studies is a lack of replication for the same alleles in the same direction and the same haplotypes across the studies. In addition, recent genome-wide association studies (GWAS)^{6, 7} as well as a large association study⁸ and a meta-analysis of variants in the DISC1 gene⁹ failed to replicate significant associations of the DISC1 gene with SCZ. The second concern is a gender-specific association of DISC1 in SCZ. A meta-analysis of published literature has demonstrated a sex difference in the risk of developing SCZ,¹⁰ and several studies have demonstrated sex-specific associations of DISC1 in SCZ.³ However, the GWAS has produced evidence that the genetic basis of SCZ is the same in males and females.¹¹ When the data are subdivided on the basis of sex in genetic association studies, one major problem that arises is the lack or reduction of power, and another is to claim nominal statistical significance, which may be occurred by chance. The sample size of the present study was small, and most of their sex-specific findings did not remain significant after correction for multiple comparisons.⁴ Patsopoulos et al.¹² empirically evaluated observational 432 studies claiming to have found sex-related differences in genetic effects for common diseases and traits, and demonstrated that the majority of these claims were insufficiently documented or spurious. The third concern is a genetic overlap between SCZ and BPAD in the DISC1 gene. As described above, the translocation event involving DISC1 increases the risk of both SCZ and BPAD.^{1, 2} Lichtenstein et al.¹³ reported that first-degree relatives of probands with either SCZ or BPD were at increased risk of these disorders, and half-siblings had an increased risk, but lower than that of the full-siblings, suggesting that SCZ and BPD partly share a common genetic cause. Similar to this epidemiological study, the GWAS revealed that common polygenic variation contributed to the risk of SCZ and BPD.⁶ From this point of view, the present study’s finding of a genetic overlap between SCZ and BPAD in the DISC1 gene⁴ is not surprising.

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