Hypothesis-driven candidate genes for schizophrenia compared to genome-wide association results.
Hypothesis-driven candidate genes for schizophrenia compared to genome-wide association results.
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DOI：
10.1017/s0033291711001607
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发表时间：
2012-03
影响因子：
6.9
通讯作者：
Sullivan, P. F.
中科院分区：
文献类型：
--
作者：
Collins, A. L.;Kim, Y.;Sklar, P.;O'Donovan, M. C.;Sullivan, P. F.
关键词：
候选基因研究是精神分裂症遗传学研究的重要途径。这些研究的结果一直令人困惑，没有明确的基因牵连。假设驱动的候选基因文献可以通过与全基因组关联研究（GWAS）的结果进行比较来评估。我们描述了来自SZGene的假设驱动的候选基因研究的特征，并使用通路分析将假设驱动的候选基因与来自国际精神分裂症联盟（ISC）的GWAS结果进行比较。SZGene包含在1，374项研究中评估的732个常染色体基因。这些基因在检测人类疾病的典型遗传效应方面的统计能力很差，仅评估了基因组中3.7%的基因，并且每个基因的标记密度很低。大多数基因被评估了一次或两次（76.9%），提供了最小的能力来评估跨研究的共识。ISC有89%的能力检测常见人类疾病的典型遗传效应，并评估了79%的已知常染色体常见遗传变异。通路分析没有显示在假设驱动的候选基因中更小的ISC p值的富集，也没有对驱动候选基因选择的元假设进行全面评估（精神分裂症是突触或神经发育的疾病）。大多数研究的假设驱动的候选基因没有显著的ISC结果（COMT，DRD3，DRD2，HTR2A，NRG 1，BDNF，DTNBP1和SLC6A4）。我们没有发现支持的想法，假设驱动的候选基因在文献中研究的精神分裂症的病因学所涉及的共同变异丰富。需要更大的样本来明确评估这一结论。
Candidate gene studies have been a key approach to the genetics of schizophrenia. Results of these studies have been confusing and no genes have been unequivocally implicated. The hypothesis-driven candidate gene literature can be appraised via comparison with the results of genome-wide association studies (GWAS). We described the characteristics of hypothesis-driven candidate gene studies from SZGene, and used pathway analysis to compare hypothesis-driven candidate genes with GWAS results from the International Schizophrenia Consortium (ISC). SZGene contained 732 autosomal genes evaluated in 1,374 studies. These genes had poor statistical power to detect genetic effects typical for human diseases, assessed only 3.7% of genes in the genome, and had low marker densities per gene. Most genes were assessed once or twice (76.9%), providing minimal ability to evaluate consensus across studies. The ISC had power of 89% to detect a genetic effect typical for common human diseases and assessed 79% of known autosomal common genetic variation. Pathway analyses did not reveal enrichment of smaller ISC p-values in hypothesis-driven candidate genes nor did a comprehensive evaluation of meta-hypotheses driving candidate gene selection (schizophrenia as a disease of the synapse or neurodevelopment). The most studied hypothesis-driven candidate genes had no notable ISC results (COMT, DRD3, DRD2, HTR2A, NRG1, BDNF, DTNBP1, and SLC6A4). We did not find support for the idea that the hypothesis-driven candidate genes studied in the literature were enriched for common variation involved in the etiology of schizophrenia. Larger samples are required definitively to evaluate this conclusion.