Genome-wide Association Study Identifies Genetic Variation in Neurocan as a Susceptibility Factor for Bipolar Disorder

Abstract

We conducted a genome-wide association study (GWAS) and a follow-up study of bipolar disorder (BD), a common neuropsychiatric disorder. In the GWAS, we investigated 499,494 autosomal and 12,484 X-chromosomal SNPs in 682 patients with BD and in 1300 controls. In the first follow-up step, we tested the most significant 48 SNPs in 1729 patients with BD and in 2313 controls. Eight SNPs showed nominally significant association with BD and were introduced to a meta-analysis of the GWAS and the first follow-up samples. Genetic variation in the neurocan gene (NCAN) showed genome-wide significant association with BD in 2411 patients and 3613 controls (rs1064395, p = 3.02 × 10(-8); odds ratio = 1.31). In a second follow-up step, we replicated this finding in independent samples of BD, totaling 6030 patients and 31,749 controls (p = 2.74 × 10(-4); odds ratio = 1.12). The combined analysis of all study samples yielded a p value of 2.14 × 10(-9) (odds ratio = 1.17). Our results provide evidence that rs1064395 is a common risk factor for BD. NCAN encodes neurocan, an extracellular matrix glycoprotein, which is thought to be involved in cell adhesion and migration. We found that expression in mice is localized within cortical and hippocampal areas. These areas are involved in cognition and emotion regulation and have previously been implicated in BD by neuropsychological, neuroimaging, and postmortem studies.

Genome-wide association study reveals two new risk loci for bipolar disorder

“…NCAN (neurocan) on chromosome 19p13.11 was identified as a genome-wide significant risk locus for BD in the first MooDS study 8 . In our present analysis, a SNP in strong LD with the original SNP rs1064395 (r 2 ¼ 0.96) showed a sub-genome-wide significant result (rs2011503-C, P GC ¼ 8.79 Â 10 À 8 ; OR ¼ 0.87).…”

“…Over the last 5 years, the MooDS consortium produced two waves of genome-wide data for BD. The first wave of data (Germany I) were generated for the GWAS by Cichon et al 8 and are now part of the PGC-BD GWAS data 7 . The second wave of data were generated for the present GWAS and are described below.…”

“…Canadian and Spanish data were kindly provided by Catherine Laprise (UQAC, Saguenay, Canada) and Manolis Kogevinas (CREAL, Barcelona, Spain). Genotyping of the samples Australia, Germany II, Germany III, and PGC-BD were described in previous studies 7,8,[42][43][44] . We aimed to genotype the patient and controls from the same population on the same chip type.…”

“…Motivated by this and the successes of GWAS for non-psychiatric phenotypes, a big step forward was taken through a recent large BD GWAS by the multi-national Psychiatric Genomics Consortium Bipolar Disorder Working Group (PGC-BD) 7 . We have previously published a GWAS of BD using a German sample (named Germany I) 8 that was thereafter included in the GWAS of the PGC-BD 7 and another subsequent BD GWAS 9 .…”

Assessment of first and second degree relatives of individuals with bipolar disorder shows increased genetic risk scores in both affected relatives and young At‐Risk Individuals

“…Large scale collaborative genome‐wide association studies (GWAS) have identified a number of risk loci significantly associated with bipolar disorder (BP), including ODZ4 [Sklar et al, 2011; Muhleisen et al, 2014], CACNA1C [Ferreira et al, 2008; Sklar et al, 2008], ANK3 [Ferreira et al, 2008; Schulze et al, 2009; Muhleisen et al, 2014], NCAN [Cichon et al, 2011], C15ORF53 [Ferreira et al, 2008], and DGKH [Baum et al, 2008a,2008b]. Individually, each of those genes/loci contributes only a small fraction toward overall disease risk, typically <1% of the phenotypic variance [Ferreira et al, 2008].…”