Genome-wide linkage scan of 98 bipolar pedigrees and analysis of clinical covariates

Abstract

Despite compelling evidence that genetic factors contribute to bipolar disorder (BP), attempts to identify susceptibility genes have met with limited success. This may be due to the genetic heterogeneity of the disorder. We sought to identify susceptibility loci for BP in a genome-wide linkage scan with and without clinical covariates that might reflect the underlying heterogeneity of the disorder. We genotyped 428 subjects in 98 BP families at the Center for Inherited Disease Research with 402 microsatellite markers. We first carried out a nonparametric linkage analysis with MERLIN, and then reanalyzed the data with LODPAL to incorporate clinical covariates for age at onset (AAO), psychosis and comorbid anxiety. We sought to further examine the top findings in the covariate analysis in an independent sample of 64 previously collected BP families. In the non-parametric linkage analysis, three loci were nominally significant under a narrow diagnostic model and seven other loci were nominally significant under a broader model. The top findings were on chromosomes 2q24 and 3q28. The covariate analyses yielded additional evidence for linkage on 3q28 with AAO in the primary and independent samples. Although none of the linked loci were genome-wide significant, their congruence with prior results and, for the covariate analyses, their identification in two separate samples increases the likelihood that they are true positives and deserve further investigation. These findings further demonstrate the value of considering clinical features that may reflect the underlying heterogeneity of disease in order to facilitate gene mapping.

European collaborative study of early‐onset bipolar disorder: Evidence for genetic heterogeneity on 2q14 according to age at onset

“…Only two previous genome-wide linkage studies of BP considered AAO (Faraone et al, 2004;Zandi et al, 2007). Faraone et al carried out linkage analysis using AAO as a quantitative trait in BPI families and concluded that genes localized in 12p, 14q and 15q regions influenced AAO of mania and were distinct from those influencing the liability to develop BP.…”

“…BPI, BPII and MDE are defined as distinct entities in DSM-IV, which allows a high inter-rater concordance but which was not constructed to distinguish between different clinical entities depending on distinct genetic factors. Most genome-wide linkage scans have analyzed broad, intermediate and narrow phenotypes using a gradient from MDE to BPI through BPII (Garner et al, 2001;McInnis et al, 2003;Fallin et al, 2004;Schumacher et al, 2005;Zandi et al, 2007, Vazza et al, 2007Nwulia et al, 2007;Venken et al, 2007). This phenotypic classification may not be the most appropriate for defining phenotypes for the identification of linkage regions.…”

“…These results suggest that the genetic factors involved in the EO-BPI differ from those involved in the other forms of the disease. Genetic heterogeneity according to AAO has already been considered but only in two studies (Faraone et al, 2004;Zandi et al, 2007) and has never been formally tested.…”

Sex differences in TTC12/ANKK1 haplotype associations with daily tobacco smoking in Black and White Americans

“…Any SNP deviating from HWE at p < .05 corrected for multiple comparisons, with missing data on 2% or more of participants or less than 100% concordance, was dropped from analyses per standard quality control practice (Zandi, Avramopoulos, et al, 2007;Zandi, Badner, et al, 2007;. Only one SNP, rs4938012, which deviated from HWE, was removed from the analyses as described further below.…”

Does Hypomania Distinguish Bipolar II Disorder from Major Depressive Disorder?

“…It has been suggested [3, 4] that recurrence and young onset, supported by genetic/family studies [e.g. [5,6,7,8,9]], may weigh more than polarity in subtyping mood disorders. Kraepelin’s [10] most distinguishing feature of ‘manic-depressive insanity’ was recurrence.…”