Contribution of genes in the GABAergic pathway to bipolar disorder and its executive function deficit in the Chinese Han population

Am J Med Genet B Neuropsychiatr Genet. 2018 Jan;177(1):50-67. doi: 10.1002/ajmg.b.32601. Epub 2017 Nov 14.

Abstract

In this study, we investigated the association between bipolar I disorder (BDI) and between cognitive deficits therein and SNPs in GABAergic receptor genes. The sample comprised 477 patients with BDI and 438 healthy controls, with three neurocognitive tests being administered in 123 patients and 164 controls. For three SNPs, rs505474, rs1398175, and rs4868029 in the GABRA2, GABRA4, and GABRP genes, respectively, their allele frequencies were significantly different between patients and controls (Bonferroni-adjusted p = values 3.84 × 10-4 , 9.92 × 10-3 , and 1.22 × 10-2 , respectively). Four haplotypes were significantly associated with BDI (TA and AG for rs3815762 and rs4868029 in GABRP, GG for rs11636988 and rs8024256 in GABRB3 and GAGG for rs2197414, rs4921195, rs13188991, and rs11956731 in GABRA6, with p values of 0.0038, 0.044, 0.0176, and 0.0267, respectively, on 10,000 permutations). Furthermore, the SNP (rs2912585) within 250 kb upstream of the GABRB3 gene displayed a strong association with the Tower of Hanoi (TOH) executive time in the patient group (p = 2.844 × 10-6 ). One other SNP (rs754661), which is located at the intronic region of the same gene, was associated with the global trait of the executive function and post hoc analysis showed significant SNP by group effect (p = 0.0094). Our study supports previous findings that GABAA receptor genes are associated with bipolar disorder; it also suggests that the GABAA genes, especially the GABRB3 gene, might play a role in the executive function deficit in bipolar disorder, although future replication with a larger sample size is needed.

Keywords: GABA; bipolar disorder; executive function; genetics.

MeSH terms

  • Adult
  • Alleles
  • Asian Continental Ancestry Group / genetics
  • Bipolar Disorder / genetics*
  • Cognition Disorders / genetics
  • Ethnic Groups / genetics
  • Executive Function / physiology*
  • Female
  • GABA Agents
  • GABAergic Neurons
  • Gene Frequency / genetics
  • Genetic Predisposition to Disease
  • Genotype
  • Haplotypes
  • Humans
  • Male
  • Polymorphism, Single Nucleotide / genetics
  • Receptors, GABA / genetics*
  • Receptors, GABA-A / genetics

Substances

  • GABA Agents
  • GABRA2 protein, human
  • GABRA4 protein, human
  • GABRP protein, human
  • Receptors, GABA
  • Receptors, GABA-A