Shared and specific susceptibility loci for schizophrenia and bipolar disorder: a dense genome scan in Eastern Quebec families

Abstract

The goal of this study was to identify susceptibility loci shared by schizophrenia (SZ) and bipolar disorder (BP), or specific to each. To this end, we performed a dense genome scan in a first sample of 21 multigenerational families of Eastern Quebec affected by SZ, BP or both (N ¼ 480 family members). This probably constitutes the first genome scan of SZ and BP that used the same ascertainment, statistical and molecular methods for the concurrent study of the two disorders. We genotyped 607 microsatellite markers of which 350 were spaced by 10 cM and 257 others were follow-up markers in positive regions at the 10 cM scan. Lander and Kruglyak thresholds were conservatively adjusted for multiple testings. We maximized the lod scores (mod score) over eight combinations (2 phenotype severity levels  2 models of transmission  2 analyses, affected/unaffected vs affected-only). We observed five genomewide significant linkages with mod score 44.0: three for BP (15q11.1, 16p12.3, 18q12-q21) and two for the shared phenotype, that is, the common locus (CL) phenotype (15q26,18q12-q21). Nine mod scores exceeded the suggestive threshold of 2.6: three for BP (3q21, 10p13, 12q23), three for SZ (6p22, 13q13, 18q21) and three for the CL phenotype (2q12.3, 13q14, 16p13). Mod scores 41.9 might represent confirmatory linkages of formerly reported genomewide significant findings such as our finding in 6p22.3 for SZ. Several regions appeared to be shared by SZ and BP. One linkage signal (15q26) appeared novel, whereas others overlapped formerly reported susceptibility regions. Despite the methodological limitations we raised, our data support the following trends: (i) results from several genome scans of SZ and BP in different populations tend to converge in specific genomic regions and (ii) some of these susceptibility regions may be shared by SZ and BP, whereas others may be specific to each. The present results support the relevance of investigating concurrently SZ and BP within the same study and have implications for the modelling of genetic effects. Molecular Psychiatry (2005) 10, 486-499.

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

“…We previously reported a genomewide suggestive linkage in this region with the CL phenotype in sample 1 that crossed the diagnosis boundaries by combining SZ, BP and schizoaffective disorders. 7 This initial finding was also replicated in sample 2. 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.…”

“…A first wave of collection produced a first sample of 21 kindreds (sample 1) described in Maziade et al, 7 and a second wave of data collection ended up with a second sample of 27 kindreds (sample 2) described in Merette et al 9 The combined sample of 48 multigenerational families comprises a total of 1278 individuals, 376 of whom were affected by a DSM-IV SZ or BP spectrum disorder. Lifetime DSM-III-R or DSM-IV diagnoses were made according to a stringent best-estimate lifetime procedure described in Maziade et al 10 and Roy et al 11 Using these diagnoses, six phenotypes were derived: BP narrow (BP I only, n ¼ 121), BP broad (BP I, n ¼ 121; BP II, n ¼ 34; and recurrent major depression, n ¼ 47), SZ narrow (SZ only, n ¼ 125), SZ broad (SZ, n ¼ 125; schizophrenic form, n ¼ 7; and schizotypal personality disorder, n ¼ 3), common locus (CL) narrow (BP narrow, n ¼ 121; SZ narrow, n ¼ 125; and schizoaffective disorder, n ¼ 38) and CL broad (BP broad, n ¼ 202; SZ broad, n ¼ 135; and schizoaffective disorder, n ¼ 38).…”

“…7,9 Microsatellite markers were selected from the NCBI database to produce a dense covering of the chromosomal region originally detected to be linked with SZ, BP or both in our cohort. In total, subjects were genotyped on 414 microsatellite markers on 22 chromosomes.…”

“…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.…”

A genome screen of 35 bipolar affective disorder pedigrees provides significant evidence for a susceptibility locus on chromosome 15q25-26

“…The authors discuss the unclear relationship between major depressive disorder and BP, with BPII being especially difficult to differentiate from major depressive disorder. Maziade et al 52 conducted a genome scan for shared and specific susceptibility loci for schizophrenia and BP. For a common locus phenotype definition combining the schizophrenia and bipolar phenotypes, significant evidence of linkage was found at the marker D15S1014 with a two-point LOD score of 4.55.…”