Department of Biomathematics, Faculty of Medicine, University of Thessaly, Larissa, Greece.
The Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts, USA.
Genet Test Mol Biomarkers. 2022 Feb;26(2):59-69. doi: 10.1089/gtmb.2021.0236.
Autism spectrum disorder (ASD) is a clinically and genetically heterogeneous group of pervasive neurodevelopmental disorders with a strong hereditary component. Although, genome-wide linkage scans (GWLS) and association studies (GWAS) have previously identified hundreds of ASD risk gene loci, the results remain inconclusive. We performed a heterogeneity-based genome search meta-analysis (HEGESMA) of 15 genome scans of autism and ASD. For strictly defined autism, data were analyzed across six separate genome scans. Region 7q22-q34 reached statistical significance in both weighted and unweighted analyses, with evidence of significantly low between-scan heterogeneity. For ASDs (data from 12 separate scans), chromosomal regions 5p15.33-5p15.1 and 15q22.32-15q26.1 reached significance in both weighted and unweighted analyses but did not reach significance for either low or high heterogeneity. Region 1q23.2-1q31.1 was significant in unweighted analyses with low between-scan heterogeneity. Finally, region 8p21.1-8q13.2 reached significant linkage peak in all our meta-analyses. When we combined all available genome scans (15), the same results were produced. This meta-analysis suggests that these regions should be further investigated for autism susceptibility genes, with the caveat that autism spectrum disorders have different linkage signals across genome scans, possibly because of the high genetic heterogeneity of the disease.
自闭症谱系障碍 (ASD) 是一组临床和遗传上具有明显异质性的广泛神经发育障碍，具有很强的遗传成分。尽管全基因组连锁扫描 (GWLS) 和关联研究 (GWAS) 先前已经确定了数百个 ASD 风险基因座，但结果仍不确定。我们对 15 项自闭症和 ASD 全基因组扫描进行了基于异质性的基因组搜索荟萃分析 (HEGESMA)。对于严格定义的自闭症，对六项单独的全基因组扫描进行了数据分析。区域 7q22-q34 在加权和非加权分析中均达到统计学意义，并且具有明显低的扫描间异质性的证据。对于 ASDs（来自 12 项单独扫描的数据），在加权和非加权分析中，染色体区域 5p15.33-5p15.1 和 15q22.32-15q26.1 均达到显著水平，但在低或高异质性方面均未达到显著水平。区域 1q23.2-1q31.1 在非加权分析中具有低扫描间异质性，达到显著水平。最后，区域 8p21.1-8q13.2 在我们所有的荟萃分析中都达到了显著的连锁峰。当我们将所有可用的全基因组扫描（15 个）结合起来时，得到了相同的结果。这项荟萃分析表明，这些区域应该进一步研究自闭症易感基因，需要注意的是，自闭症谱系障碍在全基因组扫描中有不同的连锁信号，可能是因为疾病的遗传异质性很高。
