DCLK1 variants are associated across schizophrenia and attention deficit/hyperactivity disorder

Abstract

Doublecortin and calmodulin like kinase 1 (DCLK1) is implicated in synaptic plasticity and neurodevelopment. Genetic variants in DCLK1 are associated with cognitive traits, specifically verbal memory and general cognition. We investigated the role of DCLK1 variants in three psychiatric disorders that have neuro-cognitive dysfunctions: schizophrenia (SCZ), bipolar affective disorder (BP) and attention deficit/hyperactivity disorder (ADHD). We mined six genome wide association studies (GWASs) that were available publically or through collaboration; three for BP, two for SCZ and one for ADHD. We also genotyped the DCLK1 region in additional samples of cases with SCZ, BP or ADHD and controls that had not been whole-genome typed. In total, 9895 subjects were analysed, including 5308 normal controls and 4,587 patients (1,125 with SCZ, 2,496 with BP and 966 with ADHD). Several DCLK1 variants were associated with disease phenotypes in the different samples. The main effect was observed for rs7989807 in intron 3, which was strongly associated with SCZ alone and even more so when cases with SCZ and ADHD were combined (P-value = 4 × 10(-5) and 4 × 10(-6), respectively). Associations were also observed with additional markers in intron 3 (combination of SCZ, ADHD and BP), intron 19 (SCZ+BP) and the 3'UTR (SCZ+BP). Our results suggest that genetic variants in DCLK1 are associated with SCZ and, to a lesser extent, with ADHD and BP. Interestingly the association is strongest when SCZ and ADHD are considered together, suggesting common genetic susceptibility. Given that DCLK1 variants were previously found to be associated with cognitive traits, these results are consistent with the role of DCLK1 in neurodevelopment and synaptic plasticity.

Figure 1. Association of DCKL1 genetic variants with psychiatric and cognitive traits.

Markers are ordered from 5′ to 3′ of the gene, anti-sense to the reference sequence. A. Representation of the genomic region covered and of 6 DCLK1 transcripts (from top to bottom: DCL, CARP, 2 short variants and 2 long variants). In addition to alternative start sites, the transcripts can be alternatively spliced for part of exon 9, for exon 19 and in the 3′UTR. B. All markers showing nominal association to psychiatric traits in this study or to cognitive traits in our previous study are displayed. Color code: yellow, P-value between 0.05 and 0.001; orange, P-value between 0.001 and 0.0001; red, P-value<0.0001; white, P-value>0.05; grey, marker not tested in this sample. The markers used in the cross-phenotype analyses are highlighted in red. C. LD between the markers used in the cross-phenotype analyses, and the markers associated with cognitive traits in our previous study . LD is displayed using a r² scale ranging from r² = 1 in black to r² = 0 in white.