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Genome-wide association study of temperament in bipolar disorder reveals significant associations with three novel Loci.

ABSTRACT: BACKGROUND:The many attempts to identify genes for bipolar disorder (BD) have met with limited success, which has generally been attributed to genetic heterogeneity and small gene effects. However, it is also possible that the categorical phenotypes used in genetic studies of BD are not the most informative or biologically relevant. Although quantitative phenotypes provide an alternative to categorical phenotypes based on diagnosis, they have not been fully exploited in BD genetics due to the lack of accessible biological measures. We have explored aspects of temperament as quantitative phenotypes that might define subtypes of BD with different clinical features and courses of illness. Temperament is a heritable personality factor that establishes the baseline level of reactivity, mood, and energy of a person. METHODS:We have performed a genome-wide association study with genotype data from the Bipolar Genome Study and 1263 bipolar subjects that had completed the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Autoquestionnaire (TEMPS-A). The TEMPS-A is designed to assess lifelong, milder aspects of bipolar symptomatology and defines five temperaments: hyperthymic, dysthymic, cyclothymic, irritable, and anxious. RESULTS:The irritable temperament produced the most significant result with a genome-wide significant p value of 1.7 × 10(-8) on chromosome 1. The hyperthymic temperament produced additional genome-wide significant p values of 4.1 × 10(-8) and 2.1 × 10(-8) on chromosomes 12 and 22, respectively. CONCLUSIONS:These results suggest that aspects of temperament might define subtypes of BD that are more clinically and genetically homogenous, which might aid in the identification of predisposing genetic variants.

SUBMITTER: Greenwood TA

PROVIDER: S-EPMC3925336 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Genome-wide association study of temperament in bipolar disorder reveals significant associations with three novel Loci.

Greenwood Tiffany A TA Akiskal Hagop S HS Akiskal Kareen K KK Kelsoe John R JR

Biological psychiatry 20120223 4

<h4>Background</h4>The many attempts to identify genes for bipolar disorder (BD) have met with limited success, which has generally been attributed to genetic heterogeneity and small gene effects. However, it is also possible that the categorical phenotypes used in genetic studies of BD are not the most informative or biologically relevant. Although quantitative phenotypes provide an alternative to categorical phenotypes based on diagnosis, they have not been fully exploited in BD genetics due t ...[more]

PMID: 22365631

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Project description:ObjectivesRecent genome-wide association studies (GWASs) have identified numerous putative genetic polymorphisms associated with bipolar disorder (BD) and/or schizophrenia (SC). We hypothesized that a portion of these polymorphisms would also be associated with BD in the Latino American population. To identify such regions, we tested previously identified genetic variants associated with BD and/or SC and ancestral haploblocks containing these single nucleotide polymorphisms (SNPs) in a sample of Latino subjects with BD.MethodsA total of 2254 Latino individuals were genotyped for 91 SNPs identified in previous BD and/or SC GWASs, along with selected SNPs in strong linkage disequilibrium with these markers. Family-based single marker and haplotype association testing was performed using the PBAT software package. Empirical P-values were derived from 10 000 permutations.ResultsAssociations of eight a priori GWAS SNPs with BD were replicated with nominal (P≤.05) levels of significance. These included SNPs within nuclear factor I A (NFIA), serologically defined colon cancer antigen 8 (SDCCAG8), lysosomal associated membrane protein 3 (LAMP3), nuclear factor kappa B subunit 1 (NFKB1), major histocompatibility complex, class I, B (HLA-B) and 5'-nucleotidase, cytosolic II (NT5C2) and SNPs within intragenic regions microRNA 6828 (MIR6828)-solute carrier family 7 member 14 (SLC7A14) and sonic hedgehog (SHH)-long intergenic non-protein coding RNA 1006 (LINC01006). Of the 76 ancestral haploblocks that were tested for associations with BD, our top associated haploblock was located in LAMP3; however, the association did not meet statistical thresholds of significance following Bonferroni correction.ConclusionsThese results indicate that some of the gene variants found to be associated with BD or SC in other populations are also associated with BD risk in Latinos. Variants in six genes and two intragenic regions were associated with BD in our Latino sample and provide additional evidence for overlap in genetic risk between SC and BD.

Dataset Information

Genome-wide association study of temperament in bipolar disorder reveals significant associations with three novel Loci.

Publications

Genome-wide association study of temperament in bipolar disorder reveals significant associations with three novel Loci.

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