KCNIP4 as a candidate gene for personality disorders and adult ADHD

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder in children with striking persistence into adulthood and a high co-morbidity with other psychiatric disorders, including personality disorders (PD). The 4p15.31 region was shown to be associated with ADHD in several genome wide association studies (GWAS). In the present study we also report association of the 4p15.31 locus with Cluster B and Cluster C PD as identified by a pooled genome-wide association study in 400 individuals suffering from PD. The gene coding for the Kv channel-interacting protein 4 (KCNIP4) is located in this region. KCNIP4 is an interaction partner of presenilin and plays a role in a negative feedback loop in the Wnt/β-catenin pathway. Thus, we reasoned it to be a promising candidate gene for ADHD as well as for PD. To clarify the role of KCNIP4 in those disorders, we conducted candidate gene based association studies in 594 patients suffering from adult ADHD and 630 PD patients as compared to 974 healthy control individuals. In the adult ADHD sample, six single markers and one haplotype block revealed to be associated with disease (p values from 0.0079 to 0.049). Seven markers within the KCNIP4 gene showed an association with PD (p values from 0.0043 to 0.0437). The results of these studies suggest a role of KCNIP4 in the etiology of ADHD, PD and other co-morbid disorders

KCNIP4 as a candidate gene for personality disorders and adult ADHD

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder in children with striking persistence into adulthood and a high co-morbidity with other psychiatric disorders, including personality disorders (PD). The 4p15.31 region was shown to be associated with ADHD in several genome wide association studies (GWAS). In the present study we also report association of the 4p15.31 locus with Cluster B and Cluster C PD as identified by a pooled genome-wide association study in 400 individuals suffering from PD. The gene coding for the Kv channel-interacting protein 4 (KCNIP4) is located in this region. KCNIP4 is an interaction partner of presenilin and plays a role in a negative feedback loop in the Wnt/?-catenin pathway. Thus, we reasoned it to be a promising candidate gene for ADHD as well as for PD. To clarify the role of KCNIP4 in those disorders, we conducted candidate gene based association studies in 594 patients suffering from adult ADHD and 630 PD patients as compared to 974 healthy control individuals. In the adult ADHD sample, six single markers and one haplotype block revealed to be associated with disease (p values from 0.0079 to 0.049). Seven markers within the KCNIP4 gene showed an association with PD (p values from 0.0043 to 0.0437). The results of these studies suggest a role of KCNIP4 in the etiology of ADHD, PD and other co-morbid disorders. Elsevier B.V. and ECNP. All rights reserved

DIRAS2 is associated with adult ADHD, related traits, and co-morbid disorders

Several linkage analyses implicated the chromosome 9q22 region in attention deficit/hyperactivity disorder (ADHD), a neurodevelopmental disease with remarkable persistence into adulthood. This locus contains the brain-expressed GTP-binding RAS-like 2 gene (DIRAS2) thought to regulate neurogenesis. As DIRAS2 is a positional and functional ADHD candidate gene, we conducted an association study in 600 patients suffering from adult ADHD (aADHD) and 420 controls. Replication samples consisted of 1035 aADHD patients and 1381 controls, as well as 166 families with a child affected from childhood ADHD. Given the high degree of co-morbidity with ADHD, we also investigated patients suffering from bipolar disorder (BD) (n=336) or personality disorders (PDs) (n=622). Twelve single-nucleotide polymorphisms (SNPs) covering the structural gene and the transcriptional control region of DIRAS2 were analyzed. Four SNPs and two haplotype blocks showed evidence of association with ADHD, with nominal p-values ranging from p=0.006 to p=0.05. In the adult replication samples, we obtained a consistent effect of rs1412005 and of a risk haplotype containing the promoter region (p=0.026). Meta-analysis resulted in a significant common OR of 1.12 (p=0.04) for rs1412005 and confirmed association with the promoter risk haplotype (OR=1.45, p=0.0003). Subsequent analysis in nuclear families with childhood ADHD again showed an association of the promoter haplotype block (p=0.02). rs1412005 also increased risk toward BD (p=0.026) and cluster B PD (p=0.031). Additional SNPs showed association with personality scores (p=0.008-0.048). Converging lines of evidence implicate genetic variance in the promoter region of DIRAS2 in the etiology of ADHD and co-morbid impulsive disorders