Chromosome 13q13–q14 locus overlaps mood and psychotic disorders: the relevance for redefining phenotype

Abstract

The nosology of major psychoses is challenged by the findings that schizophrenia (SZ) and bipolar disorder (BP) share several neurobiological, neuropsychological and clinical phenotypic characteristics. Moreover, several vulnerability loci or genes may be common to the two DSM disorders. We previously reported, in a sample of 21 kindreds (sample 1), a genome-wide suggestive linkage in 13q13 -q14 with a common locus (CL) phenotype that crossed the diagnostic boundaries by combining SZ, BP and schizoaffective disorders. Our objectives were to test phenotype specificity in a separate sample (sample 2) of 27 kindreds from Eastern Quebec and to also analyze the combined sample of 48 kindreds (1274 family members). We performed nonparametric and parametric analyses and tested as phenotypes: SZ alone, BP alone, and a CL phenotype. We replicated in sample 2 our initial finding with CL with a maximum NPL pair score of 3.36 at D13S1272 (44 Mb), only 2.1 Mb telomeric to our previous maximum result. In the combined sample, the peak with CL was at marker D13S1297 (42.1 Mb) with a NPL pair score reaching 5.21, exceeding that obtained in each sample and indicating consistency across the two samples. Our data suggest a susceptibility locus in 13q13-q14 that is shared by schizophrenia and mood disorder. That locus would be additional to another well documented and more distal 13q locus where the G72/G30 gene is mapped.

Symptom dimensions as alternative phenotypes to address genetic heterogeneity in schizophrenia and bipolar disorder

“…Some of the results obtained coincide with linkage signals previously obtained in our sample 8 and also detected in other studies such as the signal on chromosome 13q that has been widely reported in the literature (see a review of 25 studies in DeteraWadleigh and McMahon 18 ), indicating two main zones of linkage with SZ or BP: one in 13q13-q14 (E40 Mb) and another in 13q21-q33 (E95 Mb). Our data suggest that the manic symptom dimension as a phenotype may help to reconcile the findings overlapping SZ and BP from different studies or to better understand the probable heterogeneity at this locus.…”

“…In the combined sample, the linkage peak with CL at marker D13S1297 (42.1Mb) reached a parametric MOD score of 3.12 and an NPLpair Àlog 10 P-value of 5.21, exceeding that obtained in each sample and indicating consistency across the two samples. 8 Using our subtyping strategy, we found a significant linkage signal replicated across samples at marker D13S291 (44.82 Mb) reaching a MOD score of 5.20 on the second subtype identified from the mania dimension (Table 3), corresponding to a P-value of 1.0 Â 10 À6 or Àlog 10 P-value of 6.0. As seen in Figure 1a (mania subtype 2), this subtype represents a cluster of 323 subjects expressing manic symptoms (ie, who had at least a questionable level of manic symptoms).…”

“…5 In the current paper, we apply this framework to two unique SZ and BP kindreds from the Eastern Quebec population that have been submitted to different genetic analyses. [6][7][8] Our main objectives were to evaluate whether our proposed strategy would (i) lead to a better characterization of the signals than that obtained with DSM categories, (ii) allow the detection of new linkage signals and (iii) facilitate replication across two kindred samples when compared with the replication of linkage findings originally obtained with the BP or SZ diagnoses in one of the subsamples.…”

Detection of Phenotype Modifier Genes Using Two-Locus Linkage Analysis in Complex Disorders Such as Major Psychosis

“…Our group and others have extensively documented commonalities in mechanisms across SZ and BP as indicated by their familial co-aggregation [1,17] , neurocognitive and neurobiological endophenotypes [18,19] and several genetic linkage or association signals [2,[20][21][22] . In addition to genes conferring susceptibility to the broad spectrum of MP spanning SZ and BP, we hypothesize that other genes may modify the effect of these genes and lead to the specific expression of either SZ or BP.…”

“…Among the 48 kindreds, we already reported [20] that 12 of the 48 kindreds presented both SZ and BP cases in comparison to the other families that were predominantly affected by either SZ or BP, i.e. no more than 15% of patients were affected by the other disorder in a family.…”