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

Both common and rare genetic variation play a role in the causes for mood disorders. Very large families pose unique opportunities and analytical challenges but may provide a way to identify regions and mutations associated with mood disorders. We identified a family with a high prevalence (~30%) of mood disorders in a rural village in Brazil, featuring decreasing age of onset over generations. The pattern of inheritance was complex with 32 Bipolar type I cases, 11 Bipolar type II and 59 recurrent and/or severe Depression cases in addition to other phenotypes. We enrolled 333 participants with DNA samples from a broader pedigree of 960 subjects for genotyping using the Affymetrix 10K array. Non-parametric linkage was carried out via MERLIN and parametric with both MERLIN and MCLINKAGE. We exome sequenced a subset of the family (n=27) in order to identify rare variation within the linkage regions shared by affected family members. We identified four genome wide significant and four suggestive linkage regions on chromosomes 1, 2, 3, 11 and 12 for different phenotype definitions. However, no region received strong joint support in both the parametric and non-parametric analyses. Exome sequencing revealed potential deleterious variants in 11p15.4 for MDD and 1q21.1-1q21.3 and 12p23.1-p22.3, implicated in cell signaling, adhesion, translation and neurogenesis processes. Overall, our results suggest promising, but not definitive or confirmed evidence, that rare genetic variation contributes to the high prevalence of mood disorders in this multi-generational family. We note that a substantial role for common genetic variation is likely given the strength of the linkage signals observed. The World Health Organisation reports depression and bipolar disorder as the second and seventh most important causes of years lost due to disability worldwide[1]. The heritability of bipolar disorder is between 60-90% with a lower but still substantial heritability for major depression (40-45%) [2]; [3]. First-degree relatives of bipolar disorder probands have a 5-10 fold increase in risk of developing the illness compared to relatives of controls but also show a three fold increase in unipolar depression, indicating that bipolar disorder does not “breed true” [4]. Large collaborative genome-wide association studies (GWAS) have uncovered several common genetic variants of small effect [5]. Genomewide estimates of heritability suggest that up to 60% of the genetic risk is contributed by common variants [6]. Overall, the current picture for bipolar disorder (and almost all complex traits) is a genetic architecture formed of both common and rare variants. Linkage studies have been pursued on the basis that there may be variants of greater effect shared between and within affected families. However these studies have usually focused on collections of comparatively small families or sib pairs and few consistent findings have emerged [7]. Large multigenerational families (e. g. of >30 affected individuals) theoretically offer a powerful means for mapping complex disease loci that are individually rare but common in a single family. These loci may be more highly penetrant and of larger effect than loci found with GWAS [8]. Here we report the results of the Brazilian Bipolar Family (BBF) study on a five-generation family of 639 members of which 333 were enrolled in the current analyses. Our objectives were to perform a linkage analysis with genome coverage and try to identify new genes/mutations related to bipolar and other mood disorders in the family. Here we report our findings and preliminary results of sequencing of linkage regions.