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.

Genome wide association study identifies variants in NBEA associated with migraine in bipolar disorder

“…However, the close proximity makes it difficult to separate effects of the two genes (Cullinane et al, 2013; Tsang et al, 2009). Moreover, the identified associated region is also physically close to DCLK1 , a gene which has been implemented in neurodevelopment, vesicle transport, verbal memory, schizophrenia and attention deficit/hyperactivity disorder (ADHD) (Håvik et al, 2012; Smith et al, 2002). However, there is a recombination hot spot between NBEA and DCLK1 , and we found no LD between a previously reported significant SNP in DCLK1 and our top hit (r 2 = 0.001 and D′=0.035).…”

Genome-wide association study and polygenic risk score analysis for hearing measures in children

“…GWAS for normal hearing included subjects from 18 to 92 years of age [29][30][31] and implicated several genes (i.e. DCLK1, PTPRD, GRM8, CMIP, SIK3, PCDH20, SLC28A3), which have partly been associated with neurodevelopmental traits [32][33][34][35][36][37] . A case control design based on electronical health records on age-related hearing loss identified SNPs near ISG20 and TRIOBP 38 , which had previously been associated with prelingual nonsyndromic hearing loss 39 .…”

DCLK1 phosphorylates the microtubule‐associated protein MAP7D1 to promote axon elongation in cortical neurons

“…Thus, DCLK1 functions together with DCX to regulate neuronal migration and axon elongation during cortical development. Recent genome wide association studies suggest that genetic variants of DCLK1 are associated with cognitive traits, schizophrenia and attention deficit hyperactivity disorder (ADHD) (Le Hellard et al, ; Havik et al, ), supporting the significant role of DCLK1 in neuronal functions.…”