Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia.
Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia.
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DOI：
10.1186/s13229-017-0137-9
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发表时间：
2017
期刊：
影响因子：
6.2
通讯作者：
Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium
中科院分区：
文献类型：
--
作者：
Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium
在过去的十年中，全基因组关联研究（GWAS）已被应用于帮助理解性状的生物学。这种方法的成功取决于真实风险变量所携带的潜在效应量，以及在研究设计和研究样本量的情况下观察此类效应的相应统计功效。之前的ASD GWAS已经确定了全基因组显着（GWS）风险位点;然而，这些研究在较低效应量（优势比（OR）<1.15）下确定GWS位点的统计功效较低。我们进行了大规模的协调国际合作，以联合收割机独立的基因分型数据，以提高统计能力，并在强大的GWS基因座的发现援助。本研究使用来自发现样本（7387例ASD病例和8567例对照）的全基因组基因分型数据，然后对来自两个复制集（7783例ASD病例和11359例对照; 1369例ASD病例和137308例对照）的汇总统计量进行荟萃分析。我们在10q24.32处观察到一个GWS基因座，该基因座与包括PITX 3在内的几个基因重叠，PITX 3编码一种转录因子，该转录因子被鉴定为在神经元分化中发挥作用，CUEDC 2先前被报道与独立人群队列中的社交技能相关。我们还观察到与先前与精神分裂症有关的区域的重叠，这进一步得到了这些疾病之间强遗传相关性的支持（Rg = 0.23; P = 9 × 10−6）。我们进一步将这些精神病基因组学联盟（PGC）ASD GWAS数据与最近的PGC精神分裂症GWAS相结合，以确定可能在常见神经发育表型中重要的其他区域，并确定了12个新的GWS基因座。这些包括先前与ASD有关的基因座，如3 p13处的FOXP 1，3p25.3处的ATP 2B 2，以及染色体8p11.23上的“神经发育枢纽”。这项研究是正在进行的努力，以确定在ASD的共同变异信号的基础基因座的重要一步。除了新的GWS基因座，我们已经确定了一个显着的遗传相关性与精神分裂症和关联的ASD与几个神经发育相关的基因，如EXT 1，ASTN 2，MACROD 2和HDAC 4。 本文的在线版本（doi：10.1186/s13229-017-0137-9）包含补充材料，可供授权用户使用。
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). 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). We observe a GWS locus at 10q24.32 that overlaps several genes including PITX3, which encodes a transcription factor identified as playing a role in neuronal differentiation and CUEDC2 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; P = 9 × 10−6). 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 FOXP1 at 3p13, ATP2B2 at 3p25.3, and a ‘neurodevelopmental hub’ on chromosome 8p11.23. 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 EXT1, ASTN2, MACROD2, and HDAC4. The online version of this article (doi:10.1186/s13229-017-0137-9) contains supplementary material, which is available to authorized users.