Mol Autism. 2017 May 22;8:21. doi: 10.1186/s13229-017-0137-9. eCollection 2017.
BACKGROUND: Over the past decade genome-wide association studies (GWAS) have been applied to aid in the understanding of the biology of traits. The success of this approach is governed by the underlying effect sizes carried by the true risk variants and the corresponding statistical power to observe such effects given the study design and sample size under investigation. Previous ASD GWAS have identified genome-wide significant (GWS) risk loci; however, these studies were of only of low statistical power to identify GWS loci at the lower effect sizes (odds ratio (OR) <1.15). METHODS: We conducted a large-scale coordinated international collaboration to combine independent genotyping data to improve the statistical power and aid in robust discovery of GWS loci. This study uses genome-wide genotyping data from a discovery sample (7387 ASD cases and 8567 controls) followed by meta-analysis of summary statistics from two replication sets (7783 ASD cases and 11359 controls; and 1369 ASD cases and 137308 controls). RESULTS: We observe a GWS locus at 10q24.32 that overlaps several genes including , which encodes a transcription factor identified as playing a role in neuronal differentiation and previously reported to be associated with social skills in an independent population cohort. We also observe overlap with regions previously implicated in schizophrenia which was further supported by a strong genetic correlation between these disorders (Rg = 0.23; = 9 × 10). We further combined these Psychiatric Genomics Consortium (PGC) ASD GWAS data with the recent PGC schizophrenia GWAS to identify additional regions which may be important in a common neurodevelopmental phenotype and identified 12 novel GWS loci. These include loci previously implicated in ASD such as at 3p13, at 3p25.3, and a 'neurodevelopmental hub' on chromosome 8p11.23. CONCLUSIONS: This study is an important step in the ongoing endeavour to identify the loci which underpin the common variant signal in ASD. In addition to novel GWS loci, we have identified a significant genetic correlation with schizophrenia and association of ASD with several neurodevelopmental-related genes such as , , , and
背景：在过去十年中，全基因组关联研究（GWAS）已被用于帮助理解性状的生物学机制。这种方法的成功取决于真正风险变异所携带的潜在效应大小，以及在给定研究设计和样本量的情况下观察此类效应的相应统计效力。先前的自闭症谱系障碍（ASD）GWAS已经确定了全基因组显著（GWS）风险位点；然而，这些研究在识别较低效应大小（优势比（OR）<1.15）的GWS位点方面统计效力较低。 方法：我们开展了一项大规模的国际协作，整合独立的基因分型数据，以提高统计效力，并助力可靠地发现GWS位点。本研究使用了来自一个发现样本（7387例ASD病例和8567例对照）的全基因组基因分型数据，随后对来自两个重复数据集（7783例ASD病例和11359例对照；以及1369例ASD病例和137308例对照）的汇总统计数据进行荟萃分析。 结果：我们在10q24.32观察到一个GWS位点，该位点与多个基因重叠，包括 ，其编码一种被确定在神经元分化中起作用的转录因子，并且先前在一个独立人群队列中报道与社交技能相关。我们还观察到与先前涉及精神分裂症的区域存在重叠，这些疾病之间的强遗传相关性进一步支持了这一点（Rg = 0.23； = 9×10）。我们进一步将这些精神基因组学联盟（PGC）的ASD GWAS数据与最近的PGC精神分裂症GWAS数据相结合，以确定在常见神经发育表型中可能重要的其他区域，并确定了12个新的GWS位点。这些位点包括先前涉及ASD的位点，如3p13处的 、3p25.3处的 ，以及8号染色体p11.23上的一个“神经发育枢纽”。 结论：这项研究是正在进行的确定ASD中常见变异信号基础位点工作中的重要一步。除了新的GWS位点外，我们还确定了与精神分裂症的显著遗传相关性，以及ASD与几个神经发育相关基因如 、 、 和 的关联 。
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