708 Common and 2010 rare DISC1 locus variants identified in 1542 subjects: analysis for association with psychiatric disorder and cognitive traits

Abstract

A balanced t(1;11) translocation that transects the Disrupted in schizophrenia 1 (DISC1) gene shows genome-wide significant linkage for schizophrenia and recurrent major depressive disorder (rMDD) in a single large Scottish family, but genome-wide and exome sequencing-based association studies have not supported a role for DISC1 in psychiatric illness. To explore DISC1 in more detail, we sequenced 528 kb of the DISC1 locus in 653 cases and 889 controls. We report 2718 validated single-nucleotide polymorphisms (SNPs) of which 2010 have a minor allele frequency of <1%. Only 38% of these variants are reported in the 1000 Genomes Project European subset. This suggests that many DISC1 SNPs remain undiscovered and are essentially private. Rare coding variants identified exclusively in patients were found in likely functional protein domains. Significant region-wide association was observed between rs16856199 and rMDD (P=0.026, unadjusted P=6.3 × 10(-5), OR=3.48). This was not replicated in additional recurrent major depression samples (replication P=0.11). Combined analysis of both the original and replication set supported the original association (P=0.0058, OR=1.46). Evidence for segregation of this variant with disease in families was limited to those of rMDD individuals referred from primary care. Burden analysis for coding and non-coding variants gave nominal associations with diagnosis and measures of mood and cognition. Together, these observations are likely to generalise to other candidate genes for major mental illness and may thus provide guidelines for the design of future studies.

Figure 1

TRAX/DISC1 (Disrupted in schizophrenia 1) genomic and exon structure: alignment of coding and regulatory variants. (a) Three-period moving average of all single-nucleotide polymorphisms (SNPs) identified per 5 kb across the region in this study with TRAX/DISC1 intron/exons structure given to scale. Total SNP number (black), those with a minor allele frequency (MAF) of <1% SNPs (blue), those ⩾1% MAF (green), rs16856199 (arrow). For comparison, the number of SNPs identified in the 1000 genomes (red, dashed) and the number of bases repeat masked (top black) and 7x regulatory potential (top blue) are also shown. Exon and intron structure of TRAX and DISC1 are drawn to scale. (b) The position and diagnoses of exonic or regulatory SNPs. SNPs not seen previously (underlined), synonymous SNPs (black) and non-synonymous SNPs (red), stop or putative splice SNPs (green). Novel SNPs not previously reported in the European samples of the 1000 Genomes Project (v3.20101123) or the NHLBI GO Exome Sequencing Project (ESP6500) or relevant sequencing and association studies^{, , , ,} are underlined.

Figure 2

Region-wide association analysis for schizophrenia, bipolar and recurrent major depressive disorder. Nominal P-values for Fisher's exact tests are plotted against genomic location (hg18) across the TRAX/DISC1 (Disrupted in schizophrenia 1) locus. Reference lines represent 1% (dashed) and 5% (solid) region-wide empirical thresholds. Only the association of rs16856199 and recurrent major depressive disorder remains significant at the 5% threshold (arrow).

Figure 3

Segregation of the R37W polymorphism with psychiatric diagnoses in a small Scottish family. The proband of the family is indicated (arrow). The codon containing the T allele encodes for the amino acid tryptophan (W) and the codon containing the A allele encodes arginine (R). rMDD, recurrent major depressive disorder; BP2, bipolar II.