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Bipolar disorder ANK3 risk variant effect on sustained attention is replicated in a large healthy population.

ABSTRACT: Independent genome-wide association studies have implicated a common single nucleotide polymorphism within the ANK3 gene (rs10994336) in bipolar disorder (BD) susceptibility, thus establishing rs10994336 marker as a strong candidate predisposing genetic factor for BD. Furthermore, recent findings demonstrate that this variant impacts on cognitive functioning in BD patients, their unaffected relatives, and healthy controls by influencing sustained attention. Here, we aimed to replicate this finding in a large population-based sample of healthy young adults (n=1808). Sustained attention was evaluated using the Continuous Performance Test as in the original study and working memory was assessed with the n-back task. Individuals carrying the BD risk T-allele showed significantly reduced sensitivity in target detection, increased errors of commission, and atypical response latency variability. In addition, we confirmed the lack of an association between the rs10994336 variant and working memory, as well as general intellectual ability, suggesting a specific effect on the Continuous Performance Test performance.

SUBMITTER: Hatzimanolis A

PROVIDER: S-EPMC5744587 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Bipolar disorder ANK3 risk variant effect on sustained attention is replicated in a large healthy population.

Hatzimanolis Alex A Smyrnis Nikolaos N Avramopoulos Dimitrios D Stefanis Costas N CN Evdokimidis Ioannis I Stefanis Nicholas C NC

Psychiatric genetics 20120801 4

Independent genome-wide association studies have implicated a common single nucleotide polymorphism within the ANK3 gene (rs10994336) in bipolar disorder (BD) susceptibility, thus establishing rs10994336 marker as a strong candidate predisposing genetic factor for BD. Furthermore, recent findings demonstrate that this variant impacts on cognitive functioning in BD patients, their unaffected relatives, and healthy controls by influencing sustained attention. Here, we aimed to replicate this findi ...[more]

PMID: 22498896

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Project description:Genetic analyses of psychiatric illnesses, such as bipolar disorder (BPD), have revealed essential information regarding the underlying pathological mechanisms. While such studies in populations of European ancestry have achieved prominent success, understanding the genetic risk factors of these illnesses (especially BPD) in Chinese population remains an urgent task. Given the lack of genome-wide association study (GWAS) of BPD in Chinese population from Mainland China, replicating the previously reported GWAS hits in distinct populations will provide valuable information for future GWAS analysis in Han Chinese. In the present study, we have recruited 1146 BPD cases and 1956 controls from Mainland China for genetic analyses, as well as 65 Han Chinese brain amygdala tissues for mRNA expression analyses. Using this clinical sample, one of the largest Han Chinese BPD samples till now, we have conducted replication analyses of 21 single nucleotide polymorphisms (SNPs) extracted from previous GWAS of distinct populations. Among the 21 tested SNPs, 16 showed the same direction of allelic effects in our samples compared with previous studies; 6 SNPs achieved nominal significance (p < 0.05) at one-tailed test, and 2 additional SNPs showed marginal significance (p < 0.10). Aside from replicating previously reported BPD risk SNPs, we herein also report several intriguing findings: (1) the SNP rs174576 was associated with BPD in our Chinese sample and in the overall global meta-analysis, and was significantly correlated with FADS1 mRNA in diverse public RNA-seq datasets as well as our in house collected Chinese amygdala samples; (2) two (partially) independent SNPs in MAD1L1 were both significantly associated with BPD in our Chinese sample, which was also supported by haplotype analysis; (3) a rare SNP rs78089757 in 10q26.13 region was a genome-wide significant variant for BPD in East Asians, and this SNP was near monomorphic in Europeans. In sum, these results confirmed several significant BPD risk genes. We hope this Chinese BPD case-control sample and the current brain amygdala tissues (with continuous increasing sample size in the near future) will provide helpful resources in elucidating the genetic and molecular basis of BPD in this major world population.

Project description:Bipolar disorder (BD) is a chronic psychiatric disorder of public health importance affecting >1% of the Swedish population. Despite progress, patients still suffer from chronic mood switches with potential severe consequences. Thus, early detection, diagnosis and initiation of correct treatment are critical. Cultured adipocytes from 35 patients with BD and 38 healthy controls were analysed using signal pathway reporter assays, that is, protein kinase C (PKC), protein kinase A (PKA), mitogen-activated protein kinases (extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK)), Myc, Wnt and p53. The levels of activated target transcriptional factors were measured in adipocytes before and after stimulation with lithium and escitalopram. Variations were analysed in the loci of 25 different single-nucleotide polymorphisms (SNPs). Activation of intracellular signals in several pathways analysed were significantly higher in patients than in healthy controls upon drug stimulation, especially with escitalopram stimulation of PKC, JNK and Myc, as well as lithium-stimulated PKC, whereas no meaningful difference was observed before stimulation. Univariate analyses of contingency tables for 80 categorical SNP results versus diagnoses showed a significant link with the ANK3 gene (rs10761482; likelihood ratio ?(2)=4.63; P=0.031). In a multivariate ordinal logistic fit for diagnosis, a backward stepwise procedure selected ANK3 as the remaining significant predictor. Comparison of the escitalopram-stimulated PKC activity and the ANK3 genotype showed them to add their share of the diagnostic variance, with no interaction (15% of variance explained, P<0.002). The study is cross-sectional with no longitudinal follow-up. Cohorts are relatively small with no medication-free patients, and there are no 'ill patient' controls. It takes 3 to 4 weeks of culture to expand adipocytes that may change epigenetic profiles but remove the possibility of medication effects. Abnormalities in the reactivity of intracellular signal pathways to stimulation and the ANK3 genotype may be associated with pathogenesis of BD. Algorithms using biological patterns such as pathway reactivity together with structural genetic SNP data may provide opportunities for earlier detection and effective treatment of BD.

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Bipolar disorder ANK3 risk variant effect on sustained attention is replicated in a large healthy population.

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Bipolar disorder ANK3 risk variant effect on sustained attention is replicated in a large healthy population.

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