Genome-Wide Association Study of Irritable vs. Elated Mania Suggests Genetic Differences between Clinical Subtypes of Bipolar Disorder

<div><p>The use of clinical features to define subtypes of a disorder may aid in gene identification for complex diseases. In particular, clinical subtypes of mania may distinguish phenotypic subgroups of bipolar subjects that may also differ genetically. To assess this possibility, we performed a genome-wide association study using genotype data from the Bipolar Genome Study (BiGS) and subjects that were categorized as having either irritable or elated mania during their most severe episode. A bipolar case-only analysis in the GAIN bipolar sample identified several genomic regions that differed between irritable and elated subjects, the most significant of which was for 33 SNPs on chromosome 13q31 (peak p = 2×10⁻⁷). This broad peak is in a relative gene desert over an unknown EST and between the <em>SLITRK1</em> and <em>SLITRK6</em> genes. Evidence for association to this region came predominantly from subjects in the sample that were originally collected as part of a family-based bipolar linkage study, rather than those collected as bipolar singletons. We then genotyped an additional sample of bipolar singleton cases and controls, and the analysis of irritable vs. elated mania in this new sample did not replicate our previous findings. However, this lack of replication is likely due to the presence of significant differences in terms of clinical co-morbity that were identified between these singleton bipolar cases and those that were selected from families segregating the disorder. Despite these clinical differences, analysis of the combined sample provided continued support for 13q31 and other regions from our initial analysis. Though genome-wide significance was not achieved, our results suggest that irritable mania results from a distinct set of genes, including a region on chromosome 13q31.</p> </div

Summary of the observed frequencies differences of co-morbid disorders between the GAIN and TGEN samples, as well as between the underlying family and bipolar singleton samples.

<p>Key: Family refers to bipolar subjects ascertained through the collection of families for NIMH Waves 1–4. Singleton refers to bipolar subjects ascertained as singleton cases collected as part of Wave 5. Note: Significant differences in co-morbidity were not observed between bipolar subjects with irritable vs. elated mania in either sample, nor were differences observed for gender, age at interview, age at onset, age at first mania, or age at most severe mania for any comparison (i.e., irritable vs. elated mania, GAIN vs. TGEN, family vs. singleton, all p>0.10).</p

Results of the GAIN irritable vs. elated mania case-only analyses (red), the irritable mania vs. control analyses (blue), and the elated mania vs. control analyses (green) for the chromosome 13q31 region.

<p>The physical position is shown along the <i>x</i>-axis with the –log of the p value for each SNP is shown along the <i>y</i>-axis. The locations of the <i>SLITRK1</i> and <i>SLITRK6</i> genes are indicated below, along with a spliced EST.</p

Genome-wide association results of the irritable vs. elated mania case-only analyses in the GAIN sample.

<p>The physical position is shown along the <i>x</i>-axis, color-coded by chromosome, and the –log (P value) for each SNP is shown along the <i>y</i> axis, as generated by Haploview 4.0. All regions containing at least two SNPs with p<10⁻⁴ and support for association from neighboring SNPs are indicated. Key: <i>LRRC7</i> = leucine rich repeat containing 7; <i>GNAQ</i> = guanine nucleotide binding protein; <i>GPR144</i> = G protein-coupled receptor 144; <i>NRP1</i> = neuropilin 1; <i>SLITRK6</i> = slit and trk like 6; <i>GRIA3</i> = AMPA3 ionotropic glutamate receptor.</p

Details of the association results on chromosome 13 (A) and the X chromosome <i>GRIA3</i> gene region (B) in the GAIN irritable vs. elated mania case-only analysis, as generated by SNAP 2.0.

<p>The results for the chromosome 4 <i>GABRG1</i> gene region in the GAIN irritable mania vs. control analysis are shown in (C). Physical position and gene annotations according to HapMap release 22 are shown along the <i>x-axis</i>, and −log (P value) is shown on the left <i>y-axis</i>. The most significant SNP is indicated as a large red diamond, and all other SNPs are colored according to linkage disequilibrium levels (<i>r²</i>) with the primary SNP, as calculated from HapMap Release 22 CEU population data, with darker red representing higher values. Recombination rate within the CEU samples is shown on the right <i>y-axis</i> in blue. RefSeq genes are shown with all possible exons and arrows indicating transcript direction.</p

Description of the subjects in the GAIN, TGEN, and combined datasets that were available for analysis.

<p>Description of the subjects in the GAIN, TGEN, and combined datasets that were available for analysis.</p

Pervasively rhythmic clock-controlled genes associated with BD-spectrum illnesses.

<p>Data shown include 1) any gene associations with BD or BD-related illnesses as determined by SLEP search (left), 2) the best GWA p-value for a proximal SNP obtained from SLEP (middle), 3) an FDR-corrected p-value for any gene that was determined to be nominally lithium-responsive (right). Bold indicates significance after FDR correction.</p

SNPs with psychiatric illness associations and their location relative to the most proximal clock gene.

<p>The SNPs proximal to PER1 and RORC were determined to lie outside of these genes. The SNP proximal to NR1D2 was indeterminate. The remaining SNPs were determined to be located with the corresponding clock gene.</p

Summary of the extended clock gene set included in the overlap between BD-spectrum and lithium induction after FDR correction.

<p>Summary of the extended clock gene set included in the overlap between BD-spectrum and lithium induction after FDR correction.</p

Core clock genes.

<p>Data shown include 1) Any associations to BD and/or BD-spectrum illnesses as determined by SLEP search (Left) 2) The best GWA p-value for a proximal SNP obtained from SLEP (Middle) 3) A FDR corrected p-value for any gene that was determined to be nominally lithium-responsive (Right). Bold indicates significance after FDR correction.</p