Genome‐wide scan of bipolar disorder and investigation of population stratification effects on linkage: Support for susceptibility loci at 4q21, 7q36, 9p21, 12q24, 14q24, and 16p13

Abstract

Bipolar disorder (BPD) is a complex genetic disorder with cycling symptoms of depression and mania. Despite the extreme complexity of this psychiatric disorder, attempts to localize genes which confer vulnerability to the disorder have had some success. Chromosomal regions including 4p16, 12q24, 18p11, 18q22, and 21q21 have been repeatedly linked to BPD in different populations. Here we present the results of a whole genome scan for linkage to BPD in an Irish population. Our most significant result was at 14q24 which yielded a non-parametric LOD (NPL) score of 3.27 at the D14S588 marker with a nominal P-value of 0.0006 under a narrow (bipolar type I only) model of affection. We previously reported linkage to 14q22-24 in a subset of the families tested in this analysis. We also obtained suggestive evidence for linkage at 4q21, 9p21, 12q24, and 16p13, chromosomal regions that have all been previously linked to BPD. Additionally, we report on a novel approach to linkage analysis, STRUCTURE-Guided Linkage Analysis (SGLA), which is designed to reduce genetic heterogeneity and increase the power to detect linkage. Application of this technique resulted in more highly significant evidence for linkage of BPD to three regions including 16p13, a locus that has been repeatedly linked to numerous psychiatric disorders.

Identification of susceptibility loci at 7q31 and 9p13 for bipolar disorder in an isolated population

“…With the current set of markers it is impossible to identify in which side of the centromere the susceptibility region for broad mood disorder lies. This linkage finding is consistent with an Irish bipolar disorder sibling pair genome-wide scan, which identified NPL of 2.41 on 9p21-q21 [Cassidy et al, 2007], as well as with an UK-Irish bipolar disorder sibling pair genome-wide scan reporting a multipoint LOD score of 1.74 on 9p21-p12 [Lambert et al, 2005]. Chromosome 9p13 region harbors several interesting candidate genes, including contactin associated protein-like 3 (CNTNAP3) and aldehyde dehydrogenase 1B1 precursor (ALDH1B1) (Fig.…”

Suggestive evidence for linkage of ADHD features in bipolar disorder to chromosome 10p14

“…The LOD score 2.06 was not suggestive for linkage according to Lander and Kruglyak, although the simulations supported the finding with an empirical P-value of 0.001. Supportive evidence of linkage on chromosome 12q24 region with bipolar disorder has been repeatedly found in many studies of various populations, such as French Canadian isolate [Morissette et al, 1999;Shink et al, 2005], Faroe islands isolate [Degn et al, 2001], United Kingdom and Iceland [Curtis et al, 2003], Irish population [Cassidy et al, 2007] and two Danish families sample [Ewald et al, 1998[Ewald et al, , 2002. The highest peaks in the Ewald et al [2002] and Shink et al [2005] studies were at 148 cM (near D12S1639) and 142 cM (near D12S378), respectively, both of which are only 14-20 cM proximal to our peak at 162 cM (near D12S367).…”

Genome‐scan for bipolar disorder with sib‐pair families in the Sardinian population: A new susceptibility locus on chromosome 1p22–p21?

“…Interestingly, the D1S216 marker at 1p31.1 is close to the 1p22-p21 region and linkage of this region to BD using the D1S216 marker has previously been reported [Ewald et al, 1998a]. The regions identified in the present study in other chromosomes that have already been linked to BD were located on chromosomes 2q24 [Zandi et al, 2007]; 5p15, a region containing the Dopamine Transporter gene, with the same D5S417 marker [Kelsoe et al, 2001]; 7q34 [Liu et al, 2003]; 8p23 [Ophoff et al, 2002;Walss-Bass et al, 2006] and 8q24 [Cichon et al, 2001b;Badenhop et al, 2002]; 9q21 [Friddle et al, 2000] with the D9S264 marker used in the former study only 0.33 Mb apart from the D9S167 marker yielding a positive result for the present genome scan; 10q26 [Kelsoe et al, 2001;Cichon et al, 2001a;Ewald et al, 2002;McInnis et al, 2003b]; 11p15, a region harboring the Tyrosine Hydroxylase and DRD4 genes [Smyth et al, 1996;Malafosse et al, 1997;Serretti et al, 2000;McInnis et al, 2003b]; 21q21 [Cassidy et al, 2007].Besides the markers in the 1p21-p22 region showing NPLs above 3.4, several other markers were characterized by a NPL between 2.5 and 3 and a P-value <0.005, such as D1S2752 at 1p32; D7S798 at 7q34; D8S1832 at 8q24, all regions previously linked to BD, and the marker D1S214 at 1p36.31, a region that has shown suggestive linkage to BD in the present study only (Table III).In order to further exploit these results, we reanalyzed the genotyping data using allele frequency estimations calculated by the MERLIN software [Abecasis et al, 2002]. We reasoned that, since evaluated allele frequencies are closer to the real marker frequencies in the Sardinian population and are more conservative for estimating linkage, this approach allows for further assessing the relevance of the genome scan results.…”