Stage 2 of the Wellcome Trust UK–Irish bipolar affective disorder sibling-pair genome screen: evidence for linkage on chromosomes 6q16–q21, 4q12–q21, 9p21, 10p14–p12 and 18q22

We performed a linkage analysis on 23 Finnish families with bipolar disorder and originating from the North-Eastern region of Finland, using the Illumina Linkage Panel IV (6K) Array with an average intermarker spacing of 0.65 cM across the genome. We detected genome-wide significant evidence for linkage of mood disorder (bipolar disorder type I, II, or not otherwise specified, manic type of schizoaffective psychosis, cyclothymia, or recurrent depression) to chromosomes 7q31 (LOD = 3.20) and 9p13.1 (LOD = 4.02). Analyzing the best markers on the complete set of 179 Finnish bipolar families supported the findings on chromosome 9p13 (maximum LOD score of 3.02 at position 383 Mb, immediately upstream of the centromere). This region harbors several interesting candidate genes, including contactin associated protein-like 3 (CNTNAP3) and aldehyde dehydrogenase 1 (ALDH1B1). For the 7q31 locus, only one extended pedigree and ten families originating from the same late settlement region in North-Eastern Finland provided evidence for linkage, suggesting that a gene predisposing to bipolar disorder is enriched in that region. Candidate genes of interest in this locus include potassium-voltage-gated channel, member 2 (KCND2) and calcium-dependent activator protein for secretion 2 (CADPS2). The loci on the centromeric region of 9p13 and the telomeric region of 7q31 may represent susceptibility loci for mood disorder in the Finnish population.

Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 98%

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

Palo

Soronen

Silander

et al. 2009

“…This indicates our linkage finding for inattention factor is not just another finding of the same linkage of bipolar disorder. More recent stage 2 of the Wellcome Trust UK-Irish bipolar affective disorder sibling-pair genome screen study found some evidence for linkage at two spots on chromosome 10 [Lambert et al, 2005]. One is at 29 cM, which is near to our linkage peak for inattention.…”

Section: Discussionmentioning

confidence: 80%

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

Joo

Greenwood

Schork

et al. 2009

Higher rates of bipolar disorder amongst the first-degree relatives of probands with ADHD, and increased rates of ADHD in the relatives of bipolar probands have been reported in many studies. This suggests some commonality in the genetic basis for bipolar disorder and ADHD. We hypothesized that ADHD symptoms in bipolar disorder may access a quantitative subphenotype that is genetically less complex and therefore advantageous for mapping studies. The Wender Utah Rating Scale (WURS) was used to quantify ADHD features in 57 bipolar families collected for linkage studies. The factor structure of the WURS was first examined, and heritability was estimated. Linkage analysis was then conducted using the WURS total score and factor scores as quantitative traits. Three factors were identified: impulsivity and defiant behavior, mood instability and anxiety, and inattention. The total WURS and factor scores were each significantly heritable (0.34

“…BP [Millar et al, 2007] BP [Lambert et al, 2005] (Continued ) [Xing et al, 2002], I (MDD) [Novak et al, 2006;Tochigi et al, 2008] 6.5…”

Section: 87eà03 Rs10500860mentioning

confidence: 99%

Coming to grips with complex disorders: Genetic risk prediction in bipolar disorder using panels of genes identified through convergent functional genomics

Patel

Le-Niculescu

Koller

et al. 2010

We previously proposed and provided proof of principle for the use of a complementary approach, convergent functional genomics (CFG), combining gene expression and genetic data, from human and animal model studies, as a way of mining the existing GWAS datasets for signals that are there already, but did not reach significance using a genetics-only approach [Le-Niculescu et al., 2009b]. CFG provides a fit-to-disease prioritization of genes that leads to generalizability in independent cohorts, and counterbalances the fit-to-cohort prioritization inherent in classic genetic-only approaches, which have been plagued by poor reproducibility across cohorts. We have now extended our previous work to include more datasets of GWAS, and more recent evidence from other lines of work. In essence our analysis is the most comprehensive integration of genetics and functional genomics to date in the field of bipolar disorder. Biological pathway analyses identified top canonical pathways, and epistatic interaction testing inside these pathways has identified genes that merit future follow-up as direct interactors (intra-pathway epistasis, INPEP). Moreover, we have put together a panel of best P-value single nucleotide polymorphisms (SNPs), based on the top candidate genes we identified. We have developed a genetic risk prediction score (GRPS) based on our panel, and demonstrate how in two independent test cohorts the GRPS differentiates between subjects with bipolar disorder and normal controls, in both European-American and African-American populations. Lastly, we describe a prototype of how such testing could be used to categorize disease risk in individuals and aid personalized medicine approaches, in psychiatry and beyond.