Association of Genetic Risks With Autism Spectrum Disorder and Early Neurodevelopmental Delays Among Children Without Intellectual Disability
Association of Genetic Risks With Autism Spectrum Disorder and Early Neurodevelopmental Delays Among Children Without Intellectual Disability
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DOI：
10.1001/jamanetworkopen.2019.21644
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发表时间：
2020-02
影响因子：
13.8
通讯作者：
N. Takahashi;Taeko Harada;Tomoko Nishimura;Akemi Okumura;Damee Choi;Toshiki Iwabuchi;Hitoshi Kuwabara;S. Takagai;Y. Nomura;N. Takei;K. Tsuchiya
中科院分区：
文献类型：
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作者：
N. Takahashi;Taeko Harada;Tomoko Nishimura;Akemi Okumura;Damee Choi;Toshiki Iwabuchi;Hitoshi Kuwabara;S. Takagai;Y. Nomura;N. Takei;K. Tsuchiya
自闭症谱系障碍（ASD）是高度遗传的，常见的遗传变异对ASD的贡献不大。然而，来自普通人群的儿童中常见风险变异的遗传风险与ASD特征的关联尚不清楚，这些遗传风险与婴儿神经发育的关联尚未得到很好的理解。目的：在普通人群中，检测ASD多基因风险评分（PRS）是否与18个月时的神经发育进展和6岁时的ASD特征相关。设计、设置和参与者在这项队列研究中，876名儿童在日本滨松的滨松母亲和儿童出生队列中接受了ASD PRS与神经发育进展和ASD特征的相关性测试。数据收集工作于2007年12月开始，目前仍在进行中。数据分析于2019年4月至12月进行。主要结果和测量来自最大的全基因组关联研究的汇总数据用于生成ASD PRS，并计算每个结果的阈值的显著性。自闭症诊断观察计划2用于测量6岁时的ASD特征，马伦早期学习量表用于测量18个月时的神经发育进展。结果876名参与者（出生时平均[SD]胎龄为38.9 [1.6]周; 438名[50.0%]男孩; 868名[99.1%]日本人）中，分析了734名参与者。ASD PRS与ASD性状相关（R2 = 0.024; β，0.71; SE，0.24; P = 0.03）。ASD PRS与婴儿神经发育的关联在马伦早期学习量表的粗大运动（R2 = 0.015; β，-1.25; SE，0.39; P =.01）和接受性语言（R2 = 0.014; β，-1.19; SE，0.39; P =.02）得分中最为明显。基因集富集分析发现，细胞成熟（R2 = 0.057; β，− 5.28; SE，1.40; P <.001）、腺苷酸环化酶活性和环磷酸腺苷浓度（R2 = 0.064; β，− 5.30; SE 1.30; P <.001）等几种途径与ASD性状相关。与炎症相关的基因组通常富含ASD特征和粗大运动技能（例如，趋化因子基序配体2的产生：R2 = 0.051; β，− 6.04; SE，1.75; P = 0.001;单核细胞分化的调节：R2 = 0.052; β，− 6.63; SE，1.90; P = 0.001; B细胞分化：R2 = 0.051; β，7.37; SE，2.15; P = 0.001）;与ASD性状和接受性语言技能相关的神经能信号相关基因集通常富集（例如，谷氨酸分泌调节：R2 = 0.052; β，-5.82; SE，1.68; P =.001;离子型谷氨酸受体信号通路：R2 = 0.047; β，3.54; SE，1.09; P = 0.001;谷氨酸分泌的负调节：R2 = 0.045; β，-5.38; SE，1.74; P =.002）。结论和相关性在这项研究中，ASD PRS与普通人群中的ASD特征相关。ASD的遗传风险可能与某些神经发育领域的延迟有关，例如粗大运动和接受性语言技能。
IMPORTANCE Autism spectrum disorder (ASD) is highly heritable, and modest contributions of common genetic variants to ASD have been reported. However, the association of genetic risks derived from common risk variants with ASD traits in children from the general population is not clear, and the association of these genetic risks with neurodevelopment in infants has not been well understood. OBJECTIVE To test whether a polygenic risk score (PRS) for ASD is associated with neurodevelopmental progress at age 18 months and ASD traits at age 6 years among children from the general population. DESIGN, SETTING, AND PARTICIPANTS In this cohort study, 876 children in the Hamamatsu Birth Cohort for Mothers and Children in Hamamatsu, Japan, underwent testing for the association of an ASD PRS with neurodevelopmental progress and ASD traits. Data collection began in December 2007 and is ongoing. Data analysis was conducted from April to December 2019. MAIN OUTCOMES AND MEASURES Summary data from the largest genome-wide association study were used to generate ASD PRSs, and significance of thresholds was calculated for each outcome. The Autism Diagnostic Observation Schedule 2 was used to measure ASD traits at age 6 years, and the Mullen Scales of Early Learning was used to measure neurodevelopmental progress at age 18 months. RESULTS Of 876 participants (mean [SD] gestational age at birth, 38.9 [1.6] weeks; 438 [50.0%] boys; 868 [99.1%] Japanese), 734 were analyzed. The ASD PRS was associated with ASD traits (R2 = 0.024; β, 0.71; SE, 0.24; P = .03). The association of ASD PRS with infant neurodevelopment was most pronounced in gross motor (R2 = 0.015; β, −1.25; SE, 0.39; P = .01) and receptive language (R2 = 0.014; β, −1.19; SE, 0.39; P = .02) scores on the Mullen Scales of Early Learning. Gene set enrichment analyses found that several pathways, such as cell maturation (R2 = 0.057; β, −5.28; SE, 1.40; P < .001) and adenylyl cyclase activity and cyclic adenosine monophosphate concentration (R2 = 0.064; β, −5.30; SE 1.30; P < .001), were associated with ASD traits. Gene sets associated with inflammation were commonly enriched with ASD traits and gross motor skills (eg, chemokine motif ligand 2 production: R2 = 0.051; β, −6.04; SE, 1.75; P = .001; regulation of monocyte differentiation: R2 = 0.052; β, −6.63; SE, 1.90; P = .001; and B-cell differentiation: R2 = 0.051; β, 7.37; SE, 2.15; P = .001); glutamatergic signaling–associated gene sets were commonly enriched with ASD traits and receptive language skills (eg, regulation of glutamate secretion: R2 = 0.052; β, −5.82; SE, 1.68; P = .001; ionotropic glutamate receptor signaling pathway: R2 = 0.047; β, 3.54; SE, 1.09; P = .001; and negative regulation of glutamate secretion: R2 = 0.045; β, −5.38; SE, 1.74; P = .002). CONCLUSIONS AND RELEVANCE In this study, the ASD PRS was associated with ASD traits among children from the general population. Genetic risks for ASD might be associated with delays in some neurodevelopmental domains, such as gross motor and receptive language skills.