Novel linkage to chromosome 20p using latent classes of psychotic illness in 270 Irish high-density families
Novel linkage to chromosome 20p using latent classes of psychotic illness in 270 Irish high-density families
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DOI：
10.1016/j.biopsych.2007.11.023
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发表时间：
2008-07-15
影响因子：
10.6
通讯作者：
Kendler, Kenneth S.
中科院分区：
文献类型：
--
作者：
Fanous, Ayman H.;Neale, Michael C.;Kendler, Kenneth S.
背景：多项证据表明精神分裂症的临床异质性是由于遗传异质性造成的。遗传异质性可能会降低连锁和关联研究中的信噪比。因此，对临床上同质的精神病类别进行连锁研究可能会产生更大的功效来检测至少一些位点。 方法：根据精神病操作标准清单，使用潜在类别分析将来自 270 个爱尔兰高密度家庭 (N = 755) 的精神病受试者分为六类。我们启发性地称它们为躁郁症、分裂情感症、躁狂症、精神分裂狂症、赤字综合症和核心精神分裂症。后四种的患病率大于 0.08，并在 10-cM 非参数常染色体全基因组扫描中单独测试连锁。使用 200 次模拟基因组扫描确定经验显着性。结果：七个区域达到至少一种潜在类别的提示显着性的经验标准：5q23.2-q35.3、8q13.1-q23.1、10q23.33-q26.3、12q21.2-q24.32、19q13.32-q13.43、 20p13-q22.3和21q11.2-q22.3。 200 次模拟扫描中的 5 次产生了 7 个具有暗示意义的基因座（整个实验范围内的 p = .03）。此外，在 20p13-p12.2，躁狂症和精神分裂症类别分别达到了标准，而缺陷综合征则具有该基因座 28 cM 着丝粒的赔率峰值的暗示性对数。结论：使用经验得出的临床同质表型，四个染色体区域暗示性关联，但使用传统操作化标准几乎没有提供关联证据。这种方法在 20 号染色体上尤其有效，此前该染色体几乎没有产生连锁证据。未来对精神疾病的研究可能会通过使用临床同质表型来提高检测连锁或关联的能力。
Background: Several lines of evidence suggest that the clinical heterogeneity of schizophrenia is due to genetic heterogeneity. Genetic heterogeneity may decrease the signal-to-noise ratio in linkage and association studies. Therefore, linkage studies of clinically homogeneous classes of psychotic illness may result in greater power to detect at least some loci.Methods: Latent class analysis was used to divide psychotic subjects from 270 Irish high-density families (N = 755) into six classes based on the Operational Criteria Checklist for Psychotic Illness. We heuristically call them Bipolar, Schizoaffective, Mania, Schizomania, Deficit Syndrome, and Core Schizophrenia. The latter four had prevalences of greater than .08 and were individually tested for linkage in a 10-cM nonparametric autosomal genomewide scan. Empirical significance was determined using 200 simulated genome scans.Results: Seven regions achieved empirical criteria for suggestive significance for at least one latent class: 5q23.2-q35.3, 8q13.1-q23.1, 10q23.33-q26.3, 12q21.2-q24.32,19q13.32-q13.43, 20p13-q22.3, and 21q11.2-q22.3. Five of 200 simulated scans resulted in seven suggestively significant loci (experiment-wide p = .03). Furthermore, at 20p13-p12.2, the Mania and Schizomania classes individually achieved criteria, whereas Deficit Syndrome had a suggestive logarithm of the odds peak 28 cM centromeric to this locus.Conclusions: Using empirically derived, clinically homogeneous phenotypes, four chromosomal regions were suggestively linked but provided little evidence of linkage using traditional operationalized criteria. This approach was particularly fruitful on chromosome 20, which had previously yielded little evidence of linkage. Future studies of psychiatric illness may increase their ability to detect linkage or association by using clinically homogeneous phenotypes.