Genome‐wide Association Study of Autism Spectrum Disorder in the East Asian Populations

Liu, Xiaoxi; Shimada, Takafumi; Otowa, Takeshi; Wu, Yu‐Yu; Kawamura, Yoshiya; Tochigi, Mamoru; Iwata, Yasuhide; Umekage, Tadashi; Toyota, Tomoko; Maekawa, Motoko; Iwayama, Yoshimi; Suzuki, Katsuaki; Kakiuchi, Chihiro; Kuwabara, Hitoshi; Kano, Yukiko; Nishida, Hisami; Sugiyama, Toshiro; Kato, Nobuo; Chen, Chia‐Hsiang; Mori, Norio; Yamada, Kazuo; Yoshikawa, Takeo; Kasai, Kiyoto; Tokunaga, Katsushi; Sasaki, Tsukasa; Gau, Susan Shur‐Fen

doi:10.1002/aur.1536

Cited by 90 publications

(50 citation statements)

References 68 publications

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“…Rare CNVs in PTPRD have been identified in cases with OCD [29], ADHD [34] and with brain malformations at birth [35]. SNPs in PTPRD were genome-wise significantly associated with ASD [36], restless legs syndrome [37], and self-reported mood instability [38]. Ptprd-deficient mice show learning deficits and altered long-term potentiation magnitudes in hippocampal synapses [39].…”

Section: Discussionmentioning

confidence: 99%

Genome-wide Association Study of Pediatric Obsessive-Compulsive Traits: Shared Genetic Risk between Traits and Disorder

Burton

Lemire

Xiao

et al. 2019

Preprint

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This study examined the genetic correlates of obsessive-compulsive (OC) traits and their shared genetic risks with obsessive-compulsive disorder (OCD). We conducted genome-wide association analyses on OC traits in 5018 unrelated Caucasian children and adolescents. Overall OC traits and trait dimensions (e.g., cleaning/contamination) were measured with the Toronto Obsessive-Compulsive scale (TOCS). One locus tagged by rs7856850 in an intron of PTPRD (protein tyrosine phosphatase δ) was associated with OC traits at the genome-wide significance level (p=2.48x10 -8 ). A variant in GRID2 was significantly associated with only the symmetry/ordering dimension (p=3.2x10 -8 ). We tested the role of central nervous system (CNS) and glutamate gene-sets using hypothesis-driven methods. A stratified False Discovery Rate found OC traits were associated with SNPs in three CNS genes: NPAS2 (p=7.8x10 -7 ), GRID2 (p=1.6x10 -6 ) and SH3GL2 (p=1.9x10 -7 ). The combined effect of neither the CNS development nor the glutamate gene-set were associated with OC traits using the competitive gene-set test implemented with MAGMA. We replicated the SNP in PTPRD in a meta-analysis of three independent OCD case/control genome-wide datasets (p=0.0069, cases=3384, controls=8363). Polygenic risk from OC traits was significantly associated with OCD in a sample of childhood-onset OCD and vice versa (p's<0.01). OC traits were highly but not significantly correlated with OCD (rg=0.83, p=0.07). We report the first replicated genome-wide significant variant for OCD traits. Our results indicate that OC traits in the general population share genetic risk with OCD in independent samples. This study demonstrates the feasibility and power of using trait-based approaches in community samples in psychiatric genomics.

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Section: Discussionmentioning

confidence: 99%

Genome-wide Association Study of Pediatric Obsessive-Compulsive Traits: Shared Genetic Risk between Traits and Disorder

Burton

Lemire

Xiao

et al. 2019

Preprint

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“…These results suggest that the maternal circulating levels of some compounds were more highly influenced by fetal genetic factors than maternal genetics. When assessing the association between maternal circulating organohalogens and fetal SNPs, we found two loci that reached genome-wide significance: the first SNP associated with PCB187 maps to the PTPRD gene that encodes the tyrosine phosphatase receptor δ that regulates learning processes and synaptic plasticity and has recently been identified as a novel locus for ASD in Asians (Liu et al 2015b). PTPRD may localize in axons and in dendrites to regulate their elaboration in the central nervous system (Shishikura et al 2016) and it showed moderate expression in fetal trophoblasts of the placenta (see www.proteinatlas.org/ENSG00000153707-PTPRD/tissue/primary+data).…”

Section: Discussionmentioning

confidence: 99%

Independent Maternal and Fetal Genetic Effects on Midgestational Circulating Levels of Environmental Pollutants

Traglia

Croen

Lyall

et al. 2017

G3 Genes|Genomes|Genetics

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Maternal exposure to environmental pollutants could affect fetal brain development and increase autism spectrum disorder (ASD) risk in conjunction with differential genetic susceptibility. Organohalogen congeners measured in maternal midpregnancy blood samples have recently shown significant, but negative associations with offspring ASD outcome. We report the first large-scale maternal and fetal genetic study of the midpregnancy serum levels of a set of 21 organohalogens in a subset of 790 genotyped women and 764 children collected in California by the Early Markers for Autism (EMA) Project. Levels of PCB (polychlorinated biphenyl) and PBDE (polybrominated diphenyl ether) congeners showed high maternal and fetal estimated SNP-based heritability (h2g) accounting for 39–99% of the total variance. Genome-wide association analyses identified significant maternal loci for p,p′-DDE (P = 7.8 × 10−11) in the CYP2B6 gene and for BDE-28 (P = 3.2 × 10−8) near the SH3GL2 gene, both involved in xenobiotic and lipid metabolism. Fetal genetic loci contributed to the levels of BDE-100 (P = 4.6 × 10−8) and PCB187 (P = 2.8 × 10−8), near the potential metabolic genes LOXHD1 and PTPRD, previously implicated in neurodevelopment. Negative associations were observed for BDE-100, BDE153, and the sum of PBDEs with ASD, partly explained by genome-wide additive genetic effects that predicted PBDE levels. Our results support genetic control of midgestational biomarkers for environmental exposures by nonoverlapping maternal and fetal genetic determinants, suggesting that future studies of environmental risk factors should take genetic variation into consideration. The independent influence of fetal genetics supports previous hypotheses that fetal genotypes expressed in placenta can influence maternal physiology and the transplacental transfer of organohalogens.

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“…While CNTN1 and 2 have been extensively studied in the context of neurite outgrowth, fasciculation, and axon guidance, less is known about the function of CNTN3-6 (Karagogeos, 2003; Shimoda and Watanabe, 2009; Mohebiany et al, 2014). However, CNTN3-6 have been implicated as risk genes in ASD (Fernandez et al, 2004; Christian et al, 2008; Morrow et al, 2008; Glessner et al, 2009; Roohi et al, 2009; Cottrell et al, 2011; Hussman et al, 2011; van Daalen et al, 2011; Leblond et al, 2012; Prasad et al, 2012; Vaags et al, 2012; Cukier et al, 2014; Kashevarova et al, 2014; Nava et al, 2014; Poot, 2014; Hu et al, 2015; Liu et al, 2015a). CNTN4 is strongly expressed in a subset of olfactory sensory neurons where it guides proper targeting of axon terminals to the corresponding glomeruli for the formation of olfactory circuits (Kaneko-Goto et al, 2008).…”

Section: Trans-synaptic Adhesion Molecules Play Important Roles In Thmentioning

confidence: 99%

A Subset of Autism-Associated Genes Regulate the Structural Stability of Neurons

Lin

Frei

Kilander

et al. 2016

Front. Cell. Neurosci.

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Autism spectrum disorder (ASD) comprises a range of neurological conditions that affect individuals’ ability to communicate and interact with others. People with ASD often exhibit marked qualitative difficulties in social interaction, communication, and behavior. Alterations in neurite arborization and dendritic spine morphology, including size, shape, and number, are hallmarks of almost all neurological conditions, including ASD. As experimental evidence emerges in recent years, it becomes clear that although there is broad heterogeneity of identified autism risk genes, many of them converge into similar cellular pathways, including those regulating neurite outgrowth, synapse formation and spine stability, and synaptic plasticity. These mechanisms together regulate the structural stability of neurons and are vulnerable targets in ASD. In this review, we discuss the current understanding of those autism risk genes that affect the structural connectivity of neurons. We sub-categorize them into (1) cytoskeletal regulators, e.g., motors and small RhoGTPase regulators; (2) adhesion molecules, e.g., cadherins, NCAM, and neurexin superfamily; (3) cell surface receptors, e.g., glutamatergic receptors and receptor tyrosine kinases; (4) signaling molecules, e.g., protein kinases and phosphatases; and (5) synaptic proteins, e.g., vesicle and scaffolding proteins. Although the roles of some of these genes in maintaining neuronal structural stability are well studied, how mutations contribute to the autism phenotype is still largely unknown. Investigating whether and how the neuronal structure and function are affected when these genes are mutated will provide insights toward developing effective interventions aimed at improving the lives of people with autism and their families.

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Genome‐wide Association Study of Autism Spectrum Disorder in the East Asian Populations

Cited by 90 publications

References 68 publications

Genome-wide Association Study of Pediatric Obsessive-Compulsive Traits: Shared Genetic Risk between Traits and Disorder

Genome-wide Association Study of Pediatric Obsessive-Compulsive Traits: Shared Genetic Risk between Traits and Disorder

Independent Maternal and Fetal Genetic Effects on Midgestational Circulating Levels of Environmental Pollutants

A Subset of Autism-Associated Genes Regulate the Structural Stability of Neurons

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