Maziade M, Roy M-A, Chagnon Y C, Cliche D, Fournier J-P, Montgrain N, Dion C, Lavallée J-C, Garneau Y, Gingras N, Nicole L, Pirès A, Ponton A-M, Potvin A, Wallot H, Mérette C
Department of Psychiatry, Laval University, Quebec G1J 2G3, Canada.
Mol Psychiatry. 2005 May;10(5):486-99. doi: 10.1038/sj.mp.4001594.
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=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 x 2 models of transmission x 2 analyses, affected/unaffected vs affected-only). We observed five genomewide significant linkages with mod score >4.0: 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 >1.9 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.
本研究的目的是确定精神分裂症（SZ）和双相情感障碍（BP）共有的或各自特有的易感基因座。为此，我们对魁北克东部21个受SZ、BP或两者影响的多代家庭的首个样本（N = 480名家庭成员）进行了高密度基因组扫描。这可能是首次对SZ和BP进行的基因组扫描，该扫描使用相同的确定方法、统计方法和分子方法对这两种疾病进行同步研究。我们对607个微卫星标记进行了基因分型，其中350个标记间隔为10厘摩（cM），另外257个是在10 cM扫描中阳性区域的后续标记。针对多重检验，对兰德（Lander）和克鲁格利亚克（Kruglyak）阈值进行了保守调整。我们在八种组合（2种表型严重程度水平×2种传递模型×2种分析，受累/未受累与仅受累）上最大化了对数优势分数（mod分数）。我们观察到五个全基因组显著连锁，mod分数>4.0：三个与BP相关（15q11.1、16p12.3、18q12 - q21），两个与共享表型相关，即共同基因座（CL）表型（15q26、18q12 - q21）。九个mod分数超过了2.6的提示性阈值：三个与BP相关（3q21、10p13、12q23），三个与SZ相关（6p22、13q13、18q21），三个与CL表型相关（2q12.3、13q14、16p13）。mod分数>1.9可能代表先前报道的全基因组显著发现的确认性连锁，例如我们在6p22.3对SZ的发现。几个区域似乎为SZ和BP所共有。一个连锁信号（15q26）似乎是新发现的，而其他一些区域与先前报道的易感区域重叠。尽管我们提出了方法学上的局限性，但我们的数据支持以下趋势：（i）不同人群中对SZ和BP的几次基因组扫描结果倾向于在特定基因组区域汇聚；（ii）其中一些易感区域可能为SZ和BP所共有，而其他一些区域可能各自特有。目前的结果支持在同一研究中同时研究SZ和BP的相关性，并对遗传效应建模具有启示意义。
