Clustering by phenotype and genome-wide association study in autism

Narita, Akira; Nagai, Masato; Mizuno, Satoshi; Ogishima, Soichi; Tamiya, Gen; Ueki, Masao; Sakurai, Rieko; Makino, Satoshi; Obara, Taku; Ishikuro, Mami; Yamanaka, Chizuru; Matsubara, Hiroko; Kuniyoshi, Yasutaka; Murakami, Keiko; Ueno, Fumihiko; Noda, Aoi; Kobayashi, Tomoko; Kobayashi, Mika; Usuzaki, Takuma; Ohseto, Hisashi; Hozawa, Atsushi; Kikuya, Masahiro; Metoki, Hirohito; Kure, Shigeo; Kuriyama, Shinichi

doi:10.1038/s41398-020-00951-x

Cited by 34 publications

(22 citation statements)

References 50 publications

(82 reference statements)

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“…Narita et al (31) demonstrated that clustering can be used to identify subgroups that are relatively homogeneous in disease etiology. Furthermore, Xie et al (32) performed an integrated investigation based on Sherlock analysis, spatiotemporal expression patterns, expression analysis, protein-protein interactions, coexpression, and associations with brain structure, and revealed that comprehensive integrated analysis may be an effective way to identify ASD-susceptible variants. Future GWAS analyses using these new methods may lead to the discovery of novel ASD risk genes.…”

Section: Genome-wide Association Studies (Gwas)mentioning

confidence: 99%

Genetic Overlap Among Autism Spectrum Disorders and Other Neuropsychiatric Disorders

Morimoto

Yamamoto

Kanegae

et al. 2021

Autism Spectrum Disorders

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Neuropsychiatric disorders such as autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), schizophrenia, bipolar disorder, and major depressive disorder tend to be classified as distinct entities. However, increasing evidence suggests that there are overlaps among these disorders in terms of their genetic risk factors. For example, chromosomal microdeletions and duplications in 16p11.2 have been reported in individuals with ASD as well as those with schizophrenia and intellectual disability, and common copy number variations have been reported in ASD, schizophrenia, and ADHD. Genome-wide association studies have also revealed common risk variants among ASD, ADHD, bipolar disorder, depression, and schizophrenia. Moreover, next-generation sequencing techniques have revealed overlap in de novo mutations among ASD, schizophrenia, and intellectual disability. Together, these results indicate that

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Section: Genome-wide Association Studies (Gwas)mentioning

confidence: 99%

Genetic Overlap Among Autism Spectrum Disorders and Other Neuropsychiatric Disorders

Morimoto

Yamamoto

Kanegae

et al. 2021

Autism Spectrum Disorders

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“…Specific phenotypes appear to be influenced by all IgLON genes. For example, autism has been shown to be linked with the loci of NEGR1 [29] NTM/OPCML [30] and LSAMP [31]. Similarly, differences in cognitive ability have been associated with NEGR1 [32] and the loci of all IgLONs significantly associate with the educational attainment [33].…”

Section: Introductionmentioning

confidence: 99%

Alternative Promoter Use Governs the Expression of IgLON Cell Adhesion Molecules in Histogenetic Fields of the Embryonic Mouse Brain

Jagomäe

Singh

Philips

et al. 2021

IJMS

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The members of the IgLON superfamily of cell adhesion molecules facilitate fundamental cellular communication during brain development, maintain functional brain circuitry, and are associated with several neuropsychiatric disorders such as depression, autism, schizophrenia, and intellectual disabilities. Usage of alternative promoter-specific 1a and 1b mRNA isoforms in Lsamp, Opcml, Ntm, and the single promoter of Negr1 in the mouse and human brain has been previously described. To determine the precise spatiotemporal expression dynamics of Lsamp, Opcml, Ntm isoforms, and Negr1, in the developing brain, we generated isoform-specific RNA probes and carried out in situ hybridization in the developing (embryonic, E10.5, E11.5, 13.5, 17; postnatal, P0) and adult mouse brains. We show that promoter-specific expression of IgLONs is established early during pallial development (at E10.5), where it remains throughout its differentiation through adulthood. In the diencephalon, midbrain, and hindbrain, strong expression patterns are initiated a few days later and begin fading after birth, being only faintly expressed during adulthood. Thus, the expression of specific IgLONs in the developing brain may provide the means for regionally specific functionality as well as for specific regional vulnerabilities. The current study will therefore improve the understanding of how IgLON genes are implicated in the development of neuropsychiatric disorders.

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“…Recessive TENM3 mutations have been identified in syndromic microphthalmia with developmental delay and speech abnormalities, and some cases presenting with intellectual disability 52 . CNVs and noncoding variants in this locus have been previously associated with ASD 59 – 61 . Recessive mutations in DCHS1 result in Van Maldergem syndrome (MIM #601390) 53 , 54 .…”

Section: Resultsmentioning

confidence: 98%

Analysis of recent shared ancestry in a familial cohort identifies coding and noncoding autism spectrum disorder variants

et al. 2022

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Autism spectrum disorder (ASD) is a collection of neurodevelopmental disorders characterized by deficits in social communication and restricted, repetitive patterns of behavior or interests. ASD is highly heritable, but genetically and phenotypically heterogeneous, reducing the power to identify causative genes. We performed whole genome sequencing (WGS) in an ASD cohort of 68 individuals from 22 families enriched for recent shared ancestry. We identified an average of 3.07 million variants per genome, of which an average of 112,512 were rare. We mapped runs of homozygosity (ROHs) in affected individuals and found an average genomic homozygosity of 9.65%, consistent with expectations for multiple generations of consanguineous unions. We identified potentially pathogenic rare exonic or splice site variants in 12 known (including KMT2C, SCN1A, SPTBN1, SYNE1, ZNF292) and 12 candidate (including CHD5, GRB10, PPP1R13B) ASD genes. Furthermore, we annotated noncoding variants in ROHs with brain-specific regulatory elements and identified putative disease-causing variants within brain-specific promoters and enhancers for 5 known ASD and neurodevelopmental disease genes (ACTG1, AUTS2, CTNND2, CNTNAP4, SPTBN4). We also identified copy number variants in two known ASD and neurodevelopmental disease loci in two affected individuals. In total we identified potentially etiological variants in known ASD or neurodevelopmental disease genes for ~61% (14/23) of affected individuals. We combined WGS with homozygosity mapping and regulatory element annotations to identify candidate ASD variants. Our analyses add to the growing number of ASD genes and variants and emphasize the importance of leveraging recent shared ancestry to map disease variants in complex neurodevelopmental disorders.

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Clustering by phenotype and genome-wide association study in autism

Cited by 34 publications

References 50 publications

Genetic Overlap Among Autism Spectrum Disorders and Other Neuropsychiatric Disorders

Genetic Overlap Among Autism Spectrum Disorders and Other Neuropsychiatric Disorders

Alternative Promoter Use Governs the Expression of IgLON Cell Adhesion Molecules in Histogenetic Fields of the Embryonic Mouse Brain

Analysis of recent shared ancestry in a familial cohort identifies coding and noncoding autism spectrum disorder variants

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