Abstract

Single nucleotide polymorphisms (SNPs) in the tachykinin receptor 1 gene (TACR1) are nominally associated with bipolar affective disorder (BPAD) in a genome-wide association study and in several case-control samples of BPAD, alcohol dependence syndrome (ADS) and attention-deficit hyperactivity disorder (ADHD). Eighteen TACR1 SNPs were associated with BPAD in a sample (506 subjects) from University College London (UCL1), the most significant being rs3771829, previously associated with ADHD. To further elucidate the role of TACR1 in affective disorders, rs3771829 was genotyped in a second BPAD sample of 593 subjects (UCL2), in 997 subjects with ADS, and a subsample of 143 individuals diagnosed with BPAD and comorbid alcohol dependence (BPALC). rs3771829 was associated with BPAD (UCL1 and UCL2 combined: P = 2.0 × 10−3), ADS (P = 2.0 × 10−3) and BPALC (P = 6.0 × 10−4) compared with controls screened for the absence of mental illness and alcohol dependence. DNA sequencing in selected cases of BPAD and ADHD who had inherited TACR1-susceptibility haplotypes identified 19 SNPs in the promoter region, 5′ UTR, exons, intron/exon junctions and 3′ UTR of TACR1 that could increase vulnerability to BPAD, ADS, ADHD, and BPALC. Alternative splicing of TACR1 excludes intron 4 and exon 5, giving rise to two variants of the neurokinin 1 receptor (NK1R) that differ in binding affinity of substance P by 10-fold. A mutation in intron four, rs1106854, was associated with BPAD, although a regulatory role for rs1106854 is unclear. The association with TACR1 and BPAD, ADS, and ADHD suggests a shared molecular pathophysiology between these affective disorders. © 2014 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals.

Highlights

  • Bipolar affective disorder (BPAD) has a lifetime risk of up to 1.5% [Merikangas et al, 2011]

  • Neither SNP was associated with BPAD in the UCL2 sample alone but both SNPs were associated in UCL1 alone as well as in combination with UCL2

  • Position on chromosome 2; hg19 Build NCBI37, May 2009, associated gene, NM_001058: rs3771833 (T > C) 75,366,937; rs3771829 (G > C) 75,364,145. bScreened control population has been screened for a history of mental illness and drinking behavior. cUnscreened control population has not been screened for a history of mental illness and drinking behavior. dMAF, minor allele frequency. eP-value. fOR(95 % CI), odds ratio with 95% confidence intervals in parentheses. gBPAD bipolar affective disorder University College London sample numbers 1 and 2 (UCL1 & UCL2) combined. hBPALC, subsample of UCL1 BPAD with comorbid alcohol dependence syndrome. iADS, alcohol dependence syndrome University College London sample

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Summary

Introduction

Bipolar affective disorder (BPAD) has a lifetime risk of up to 1.5% [Merikangas et al, 2011]. Alcohol dependence syndrome (ADS) is strongly comorbid with BPAD, with 38–50% of bipolar cases having a diagnosis of an alcohol use disorder [Angst et al, 2006; Goldstein et al, 2006]. A genome wide association study (GWAS) of combined alcohol dependence syndrome and bipolar disorder, BPALC, implicated several genes, CDH11, COL11A2, NMUR2, XPO7, and SEMA5A, which had previously been shown to be associated with ADS [Lydall et al, 2011]. Several genes such as CDH13, CSMD2, GRID1, and HTR1B were implicated in susceptibility to unipolar depression comorbid with alcohol dependence [Edwards et al, 2012]. Functional magnetic resonance imaging (fMRI) responses to alcohol cues showed three of these genetic markers, which may affect TACR1 transcription and/or translation, were associated with brain regions in the mesocorticolimbic pathway [Blaine et al, 2013]

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