Genome-wide association study of temperament in bipolar disorder reveals significant associations with three novel Loci.
- Authors
- Greenwood, Tiffany A; Akiskal, Hagop S; Akiskal, Kareen K; Bipolar Genome Study; Kelsoe, John R
- Year
- 2012
- Journal
- Biological psychiatry
- PMID
- 22365631
- DOI
- 10.1016/j.biopsych.2012.01.018
- PMCID
- PMC3925336
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 Γ 10(-8) on chromosome 1. The hyperthymic temperament produced additional genome-wide significant p values of 4.1 Γ 10(-8) and 2.1 Γ 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.
Genome-wide association results for all five temperaments. The physical position is shown along the x-axis, color-coded by chromosome, and the βlog (P value) for each SNP is shown along the y-axis, as generated by Haploview 4.0. Horizontal lines indicate the p<10β4 and p<5Γ10β8 thresholds. All genic regions containing at least two SNPs with p<10β4 and support for association from neighboring SNPs are indicated and detailed in Table 2. Genic regions with at least one SNP meeting the genome-wide significance criteria of p<5Γ10β8 are highlighted in blue.
Details of the genome-wide significant associated regions for the hyperthymic temperament on chromosomes 12 (a) and 22 (b) and for the irritable temperament on chromosome 1 (c). Physical position and gene annotations according to HapMap release 22 are shown along the x-axis, and βlog (P value) is shown on the left y axis. Recombination rate within the CEU samples is shown on the right y-axis in blue. The most significant SNP for each region is indicated as a large red diamond, and all other SNPs are colored according to linkage disequilibrium levels (r2) with the primary SNP, as calculated from HapMap Release 22 CEU population data, with darker red representing higher values. RefSeq genes are shown with all possible exons and arrows indicating transcript direction.
Details of the LRRC4C gene region on chromosome 11p12 and the association results for the hyperthymic, dysthymic, and cyclothymic temperaments. Physical position and gene annotations according to HapMap release 22 are shown along the x-axis. The βlog (P value) is shown on the y axis for each temperament with the hyperthymic results in red, the dysthymic results in blue, and the cyclothymic results in green. The pattern of Linkage disequilibrium across the region is presented as determined from the HapMap Release 22 CEU population data. RefSeq genes are shown with all possible exons and arrows indicating transcript direction.
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