Genetic association of the tachykinin receptor 1 TACR1 gene in bipolar disorder, attention deficit hyperactivity disorder, and the alcohol dependence syndrome. Issue 4 (9th May 2014)

• Record Type: Journal Article
• Authors: Sharp, Sally I.; McQuillin, Andrew; Marks, Michael; Hunt, Stephen P.; Stanford, S. Clare; Lydall, Greg J.; Morgan, Marsha Y.; Asherson, Philip; Curtis, David; Gurling, Hugh M. D.
• Is Part Of: American journal of medical genetics. Volume 165:Issue 4(2014)
• Page Start: 373
• Page End: 380
• Publication Date: 2014-05-09
• Subjects: Neuropsychiatry -- Periodicals; Medical genetics -- Periodicals; 616.8904205
• DOI: 10.1002/ajmg.b.32241
• Languages: English
• ISSNs: 1552-4841

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="ajmgb32241-sec-0001" sec-type="section"> <p>Single nucleotide polymorphisms (SNPs) in the tachykinin receptor 1 gene (<italic>TACR1</italic>) 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 <italic>TACR1</italic> 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 <italic>TACR1</italic> 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: <italic>P</italic> = 2.0 × 10<sup>−3</sup>), ADS (<italic>P</italic> = 2.0 × 10<sup>−3</sup>) and BPALC (<italic>P</italic> = 6.0 × 10<sup>−4</sup>) 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 <italic>TACR1</italic>‐susceptibility haplotypes identified 19 SNPs in the promoter region, 5′ UTR, exons, intron/exon junctions and 3′ UTR of <italic>TACR1</italic> that could increase vulnerability to BPAD, ADS, ADHD, and BPALC. Alternative splicing of <italic>TACR1</italic> 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 <italic>TACR1</italic> 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.</p> </sec> </abstract>