Biological Psychiatry Laboratory, Department of Psychiatry, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
FASEB J. 2011 Nov;25(11):4011-23. doi: 10.1096/fj.11-184937. Epub 2011 Jul 27.
While the use of population-based samples is a common strategy in genome-wide association studies (GWASs), family-based samples have considerable advantages, such as robustness against population stratification and false-positive associations, better quality control, and the possibility to check for both linkage and association. In a genome-wide linkage study of schizophrenia in Arab-Israeli families with multiple affected individuals, we previously reported significant evidence for a susceptibility locus at chromosome 6q23.2-q24.1 and suggestive evidence at chromosomes 10q22.3-26.3, 2q36.1-37.3 and 7p21.1-22.3. To identify schizophrenia susceptibility genes, we applied a family-based GWAS strategy in an enlarged, ethnically homogeneous, Arab-Israeli family sample. We performed genome-wide single nucleotide polymorphism (SNP) genotyping and single SNP transmission disequilibrium test association analysis and found genome-wide significant association (best value of P=1.22×10(-11)) for 8 SNPs within or near highly reasonable functional candidate genes for schizophrenia. Of particular interest are a group of SNPs within and flanking the transcriptional factor LRRFIP1 gene. To determine replicability of the significant associations beyond the Arab-Israeli population, we studied the association of the significant SNPs in a German case-control validation sample and found replication of associations near the UGT1 subfamily and EFHD1 genes. Applying an exploratory homozygosity mapping approach as a complementary strategy to identify schizophrenia susceptibility genes in our Arab Israeli sample, we identified 8 putative disease loci. Overall, this GWAS, which emphasizes the important contribution of family based studies, identifies promising candidate genes for schizophrenia.
虽然基于人群的样本是全基因组关联研究（GWAS）中的常用策略，但基于家族的样本具有相当多的优势，例如能够抵抗群体分层和假阳性关联，具有更好的质量控制，并且有可能同时检查连锁和关联。在对有多个受影响个体的阿拉伯-以色列家庭进行的精神分裂症全基因组连锁研究中，我们之前报告了在染色体 6q23.2-q24.1 上存在易感性位点的显著证据，以及在染色体 10q22.3-26.3、2q36.1-37.3 和 7p21.1-22.3 上存在提示性证据。为了鉴定精神分裂症易感基因，我们在一个扩大的、种族同质的、阿拉伯-以色列家庭样本中应用了基于家族的 GWAS 策略。我们进行了全基因组单核苷酸多态性（SNP）基因分型和单 SNP 传递不平衡测试关联分析，发现了 8 个 SNP 在全基因组范围内具有显著相关性（最佳 P 值=1.22×10(-11))，这些 SNP 位于或靠近精神分裂症的高度合理的功能候选基因内或附近。特别有趣的是一组位于转录因子 LRRFIP1 基因内和周围的 SNP。为了确定这些显著关联在阿拉伯-以色列人群之外的可复制性，我们在德国病例对照验证样本中研究了这些显著 SNP 的关联，发现了 UGT1 亚家族和 EFHD1 基因附近的关联复制。应用探索性纯合性映射方法作为补充策略，以鉴定我们的阿拉伯-以色列样本中的精神分裂症易感基因，我们鉴定了 8 个可能的疾病位点。总的来说，这项 GWAS 强调了基于家族的研究的重要贡献，确定了精神分裂症的有希望的候选基因。
