Autism spectrum disorder (ASD) has phenotypically and genetically heterogeneous characteristics. A simulation study demonstrated that attempts to categorize patients with a complex disease into more homogeneous subgroups could have more power to elucidate hidden heritability. We conducted cluster analyses using the k-means algorithm with a cluster number of 15 based on phenotypic variables from the Simons Simplex Collection (SSC). As a preliminary study, we conducted a conventional genome-wide association study (GWAS) with a data set of 597 ASD cases and 370 controls. In the second step, we divided cases based on the clustering results and conducted GWAS in each of the subgroups vs controls (cluster-based GWAS). We also conducted cluster-based GWAS on another SSC data set of 712 probands and 354 controls in the replication stage. In the preliminary study, which was conducted in conventional GWAS design, we observed no significant associations. In the second step of cluster-based GWASs, we identified 65 chromosomal loci, which included 30 intragenic loci located in 21 genes and 35 intergenic loci that satisfied the threshold of P < 5.0 × 10 −8. Some of these loci were located within or near previously reported candidate genes for ASD: CDH5,

Background: Autism spectrum disorder (ASD) has phenotypically and genetically heterogeneous characteristics. A simulation study demonstrated that attempts to categorize patients with a complex disease into more homogeneous subgroups could have more power to elucidate hidden heritability. Methods:We conducted cluster analyses using the k-means algorithm with a cluster number of 15 based on phenotypic variables from the Simons Simplex Collection (SSC). As a preliminary study, we conducted a conventional genome-wide association study (GWAS) with a dataset of 597 ASD cases and 370 controls. In the second step, we divided cases based on the clustering results and conducted GWAS in each of the subgroups vs controls (cluster-based GWAS). We also conducted cluster-based GWAS on another SSC dataset of 712 probands and 354 controls in the replication stage. Results:In the preliminary study, we observed no significant associations. In the second step of cluster-based GWASs, we identified 65 chromosomal loci, which included 30 intragenic loci located in 21 genes and 35 intergenic loci that satisfied the threshold of P<5.0×10 −8 . Some of these loci were located within or near previously reported candidate genes for ASD: CDH5, CNTN5, CNTNAP5, DNAH17, DPP10, DSCAM, FOXK1, GABBR2, GRIN2A5, ITPR1, NTM, SDK1, SNCA and SRRM4. Of these 65 significant chromosomal loci, rs11064685 located within the SRRM4 gene had a significantly different distribution in the cases vs. controls in the replication cohort. Conclusions:These findings suggest that clustering may successfully identify subgroups with relatively homogeneous disease etiologies. Further cluster validation and replication studies are warranted in larger cohorts.

Aim An association between maternal psychological distress and children's development has been reported, but  reports from Japan are limited. This study aimed to examine the association of maternal psychological distress with children's neurodevelopment in Japan. Methods The study assessed data of 7646 mother–infant pairs in the Japanese population. We used Kessler Psychological Distress Scale, a screening tool for psychological distress, to assess maternal psychological distress in early pregnancy and 2 years postpartum and divided it into four categories: none in both the pre‐natal and post‐natal periods, only the pre‐natal period, only the post‐natal period and both the pre‐natal and post‐natal periods. Children's neurodevelopment was assessed using the Ages & Stages Questionnaires Third Edition (ASQ‐3) at 4 years of age. ASQ‐3 comprises five domains (communication, gross motor, fine motor, problem solving and personal–social), and the score of less than −2 standard deviation relative to the mean in reference was defined as having developmental delay. We conducted multivariate logistic regression analysis to examine the association between maternal psychological distress and children's neurodevelopment. Results The prevalence of developmental delay of communication, gross motor, fine motor, problem solving and personal–social were 4.0%, 4.3%, 4.9%, 3.8% and 4.6%, respectively. Maternal psychological distress in only the postpartum period and both pre‐natal and postpartum periods were associated with risks of developmental delay in all domains. Maternal psychological distress in only the pre‐natal period was associated with developmental delay in communication. Conclusions Maternal psychological distress is associated with risks of children's developmental delay.