Genome-Wide Linkage Scan of Bipolar Disorder in a Colombian Population Isolate Replicates Loci on Chromosomes 7p21–22, 1p31, 16p12 and 21q21–22 and Identifies a Novel Locus on Chromosome 12q

Abstract

Background/Aims: Bipolar disorder (BP) is a severe psychiatric illness, characterised by alternating episodes of depression and mania, which ranks among the top ten causes of morbidity and life-long disability world-wide. We have previously performed a whole-genome linkage scan on 6 pedigrees segregating severe BP from the well-characterised population isolate of Antioquia, Colombia. We recently collected genotypes for the same set of 382 autosomal microsatellite markers in 9 additional Antioquian BP pedigrees. Here, we report the analysis of the combined pedigree set. Methods: Linkage analysis using both parametric and nonparametric approaches was conducted for 3 different diagnostic models: severe BP only (BPI); mood disorders (BPI, BPII and major depression); and psychosis (operationally defined by the occurrence of at least 1 episode of hallucinations and/or delusions). Results and Conclusion: For BPI only, the most interesting result was obtained for chromosome 7p21.1–p22.2 under a recessive model of inheritance (heterogeneity LOD score = 2.80), a region that had previously been linked to BP in a study on Portuguese Island families. For both BPI and mood disorders, nonparametric analyses identified a locus on chromosome 12ct–q14 (nonparametric linkage = 2.55 and 2.35, respectively). This locus has not previously been reported as a candidate region for BP. Additional candidate regions were found on chromosomes 1p22–31 (mood disorders) and 21q21–22 (BPI), 2 loci that have repeatedly been implicated in BP susceptibility. Linkage analysis of psychosis as a phenotype identified candidate regions on chromosomes 2q24–31 and 16p12–q12. The finding on chromosome 16p is noteworthy because the same locus has been implicated by genome-wide association analyses of BP.

Multisystem Component Phenotypes of Bipolar Disorder for Genetic Investigations of Extended Pedigrees

“…Previously described pedigrees, including many of those evaluated here 25–28 , show BP segregation patterns suggesting the transmission of high-impact risk-alleles. However, linkage studies of such pedigrees have yielded equivocal results, presumably because BP is genetically complex even within these families 3 .…”

“…We investigated pedigrees from ANT (11) and CVCR (15), ascertained in previous genetic studies 25–28,32–36 through hospitals and clinics in each country, utilizing genealogic information to extend each pedigree. To prioritize pedigree branches for quantitative phenotyping we recruited nuclear families including at least one member with known BP-I (based on the Diagnostic Interview for Genetics Studies, DIGS 37,38 , and/or extensive medical records), available parents, and at least two non-BP-I siblings (see Supplementary Material, e1.1 for additional details).…”

Neuroticism Mediates the Effect of P2rx7 on Outcomes of Mood Disorders

“…[1] In genome-wide association and linkage studies, 12q has been associated with MDD, [2] BD, [3] neuroticism, [4] alcoholism, [5] panic disorder, [6] and mood disorders and alcoholism. [1] In genome-wide association and linkage studies, 12q has been associated with MDD, [2] BD, [3] neuroticism, [4] alcoholism, [5] panic disorder, [6] and mood disorders and alcoholism.…”

Whole genome linkage analysis in a large Brazilian multigenerational family reveals distinct linkage signals for Bipolar Disorder and Depression

“…The linkage peak on 12p13.32 had been previously implicated in both BPD and schizophrenia. This region was implicated in general mood disorders in a study of Columbian bipolar families [35]. The second most significant linkage region was found on chromosome 3p25.3-p24.1 identified using the narrow phenotype model and a dominant mode of inheritance.…”