Common variation contributes to the genetic architecture of social communication traits.
Common variation contributes to the genetic architecture of social communication traits.
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DOI：
10.1186/2040-2392-4-34
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发表时间：
2013-09-18
期刊：
影响因子：
6.2
通讯作者：
Smith GD
中科院分区：
文献类型：
--
作者：
St Pourcain B;Whitehouse AJ;Ang WQ;Warrington NM;Glessner JT;Wang K;Timpson NJ;Evans DM;Kemp JP;Ring SM;McArdle WL;Golding J;Hakonarson H;Pennell CE;Smith GD
社会沟通困难代表了一种自闭症特征，这种特征在发展过程中具有高度遗传性和持续性。然而，人们对这种表型的潜在遗传结构知之甚少。我们使用儿童沟通检查表（10至11岁）中的项目对父母报告的社会沟通问题进行了全基因组关联研究，研究单个和/或联合标记效应。分析在一个大型的英国人口为基础的出生队列（雅芳纵向研究的父母和他们的孩子，ALSPAC，N = 5,584）和随访的样本中的儿童具有可比的措施从西澳大利亚州（RAINE，N = 1364）。在RAINE中，我们的7个独立的顶部信号中有2个（P-发现<1.0E-05）被复制（0.009 <P-复制≤0.02），并提出了在6p22.1（rs 9257616，meta-P = 2.5E-07）和14q22.1（rs 2352908，meta-P = 1.1E-06）相关的证据。在6p22.1的信号被确定在嗅觉受体基因簇内的更广泛的主要组织相容性复合体（MHC）区域。该基因组区域内最强的候选基因座是TRIM 27。该基因编码泛素E3连接酶，其是甲基-CpG结合结构域（MBD）蛋白质（例如MBD 3和MBD 4）的相互作用伴侣，并且MBD 3和MBD 4内的罕见蛋白质编码突变与自闭症有关。在14q22.1的信号被发现在一个基因贫乏的区域。ALSPAC中狭义遗传力的估计补充了单变异的发现，这表明社会沟通性状中约五分之一的表型方差是由整个基因组中基因型单核苷酸多态性的联合加性效应引起的（h2（SE）= 0.18（0.066），P = 0.0027）。总的来说，我们的研究提供了共同的和单一的SNP为基础的证据，共同的多态性的贡献，在社会沟通表型的变化。
Social communication difficulties represent an autistic trait that is highly heritable and persistent during the course of development. However, little is known about the underlying genetic architecture of this phenotype. We performed a genome-wide association study on parent-reported social communication problems using items of the children’s communication checklist (age 10 to 11 years) studying single and/or joint marker effects. Analyses were conducted in a large UK population-based birth cohort (Avon Longitudinal Study of Parents and their Children, ALSPAC, N = 5,584) and followed-up within a sample of children with comparable measures from Western Australia (RAINE, N = 1364). Two of our seven independent top signals (P-discovery <1.0E-05) were replicated (0.009 <P-replication ≤0.02) within RAINE and suggested evidence for association at 6p22.1 (rs9257616, meta-P = 2.5E-07) and 14q22.1 (rs2352908, meta-P = 1.1E-06). The signal at 6p22.1 was identified within the olfactory receptor gene cluster within the broader major histocompatibility complex (MHC) region. The strongest candidate locus within this genomic area was TRIM27. This gene encodes an ubiquitin E3 ligase, which is an interaction partner of methyl-CpG-binding domain (MBD) proteins, such as MBD3 and MBD4, and rare protein-coding mutations within MBD3 and MBD4 have been linked to autism. The signal at 14q22.1 was found within a gene-poor region. Single-variant findings were complemented by estimations of the narrow-sense heritability in ALSPAC suggesting that approximately a fifth of the phenotypic variance in social communication traits is accounted for by joint additive effects of genotyped single nucleotide polymorphisms throughout the genome (h2(SE) = 0.18(0.066), P = 0.0027). Overall, our study provides both joint and single-SNP-based evidence for the contribution of common polymorphisms to variation in social communication phenotypes.
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