Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks

Ruzzo, Elizabeth K.; Pérez-Cano, Laura; Jung, Jae-Yoon; Wang, Lee-kai; Kashef-Haghighi, Dorna; Hartl, Christopher; Singh, Chanpreet; Xu, Jin; Hoekstra, Jackson N.; Leventhal, Olivia; Leppä, Virpi; Gandal, Michael J.; Paskov, Kelley; Stockham, Nate; Polioudakis, Damon; Lowe, Jennifer K.; Prober, David A.; Geschwind, Daniel H.; Wall, Dennis P.

doi:10.1016/j.cell.2019.07.015

Cited by 366 publications

(427 citation statements)

References 111 publications

(178 reference statements)

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“…C4A co-expression partners at FDR q-value < 0.5 were assessed for enrichment of rare variants identified in neurodevelopmental disorders. These included: ~100 high-confidence autism spectrum disorder (ASD) risk genes harboring rare de novo variants 56,57 ; ASD risk genes harboring rare inherited variants 58 ; genes harboring recurrent de novo copy number variants associated with ASD or SCZ, as compiled in ref 21 ; genes harboring an excess of rare exonic variants in ASD, SCZ, intellectual disability (ID), developmental delay (DD), and epilepsy as assessed through an extended version of transmission and de novo association test (extTADA) 59 ; syndromic and highly ranked (1 and 2) genes from SFARI Gene database; genes harboring disruptive and damaging ultra-rare variants (dURVs) in SCZ 60 ; a list of high-confidence epilepsy risk genes compiled in ref 61 ; 321 high-confidence SCZ risk genes identified in ref 18 ; ten high-confidence SCZ risk genes harboring rare exonic variants as identified by the SCHEMA consortium ( https://schema.broadinstitute.org /). For binary gene sets, statistical enrichment analyses were performed using logistic regression, correcting for linear-and log-transformed gene and transcript lengths as well as GC content.…”

Section: Rare Variant Enrichmentmentioning

confidence: 99%

Brain gene co-expression networks link complement signaling with convergent synaptic pathology in schizophrenia

Kim

Haney

Zhang

et al. 2020

Preprint

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Genome-wide association studies have successfully identified hundreds of genomic regions associated with schizophrenia (SCZ). Subsequent fine-mapping of the strongest association signal, which lies in the major histocompatibility complex (MHC) locus, found that risk for SCZ is partially mediated by complex structural variation of the complement component 4 ( C4 ) genes and resulting increased expression of C4A . Although C4A is believed to partake in synaptic pruning, its precise function in the human brain-and its relation to other SCZ risk factors-remains difficult to examine, due to lack of an appropriate experimental system and lack of evolutionary conservation in model organisms. Here we perform a large-scale functional genomic investigation of the human frontal cortex to characterize the systems-level architecture of C4A co-expression and how this network is remodeled with increased C4A copy number. We identify a putative transcriptomic signature of synaptic pruning as well as spatiotemporal and sex differences in C4A co-expression with largest effects observed in frontal cortical brain regions of middle-aged males. We also find that negative, but not positive, co-expression partners of C4A exhibit substantial enrichment for SNP-heritability in SCZ. In line with this finding, there is limited evidence that the complement system is a core SCZ-relevant pathway in comparison to synaptic components. Overall, our results highlight human brain-specific function of C4A and strong and specific convergence of polygenic effects in SCZ pathophysiology.

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Section: Rare Variant Enrichmentmentioning

confidence: 99%

Brain gene co-expression networks link complement signaling with convergent synaptic pathology in schizophrenia

Kim

Haney

Zhang

et al. 2020

Preprint

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“…Furthermore, while most autism sequencing studies have primarily focused on identifying de novo alterations in simplex families, we sought to identify inherited alterations that may contribute to autism risk [Cukier et al, ]. This report focuses on one family in which three brothers with autism who all carry a stop‐gain alteration in nuclear receptor subfamily 3 group C member 2 ( NR3C2 ), a gene previously connected with autism [De Rubeis et al, ; Iossifov et al, ; Ruzzo et al, ; Turner et al, ]. NR3C2 encodes a mineralocorticoid receptor (MR) that acts as a ligand‐dependent transcription factor and functions in the hypothalamic–pituitary–adrenal (HPA) axis in response to stress [Zennaro, Souque, Viengchareun, Poisson, & Lombes, ].…”

Section: Clinical Features In Three Brothers With Autismmentioning

confidence: 99%

“…These include syndromic genes as well as genes labeled as high confidence ASD candidates (category #1), strong ASD candidates (#2), or genes with suggestive evidence (#3). Two genes with heterozygous variants met this criteria: NR3C2 ( nuclear receptor subfamily 3 group C member 2 ) and SCN1A ( sodium voltage‐gated channel alpha subunit 1 ) [Yuen et al, ; De Rubeis et al, ; Iossifov et al, ; O'Roak et al, ; Ruzzo et al, ; Toma et al, ; Turner et al, ; Weiss et al, ].…”

Section: Clinical Features In Three Brothers With Autismmentioning

confidence: 99%

“…Evidence has been accumulating over the past few years to support a role for NR3C2 in autism with other studies identifying potentially pathogenic mutations in patients (Table ) [De Rubeis et al, ; Iossifov et al, ; Ruzzo et al, ; Turner et al, ]. The first study identified two alterations in singleton individuals, p.P300R and S818X [Iossifov et al, ].…”

Section: Clinical Features In Three Brothers With Autismmentioning

confidence: 99%

“…In the third study, whole genome sequencing revealed a de novo point mutation in a putative regulatory element upstream of NR3C2 [Turner et al, ]. Lastly, two large deletions in the gene have been reported: a 848 bp deletion encompassing the first two exons of NR3C2 and a 314 kb deletion which span the first four exons, removing all known start sites [Kushima et al, ; Ruzzo et al, ]. In the gnomAD database, NR3C2 is reported to have only eight loss‐of‐function (LoF) variants, giving an observed/expected LoF variants score of 0.19 and a pLI = 0.84 [Lek et al, ].…”

Section: Clinical Features In Three Brothers With Autismmentioning

confidence: 99%

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Three Brothers With Autism Carry a Stop‐Gain Mutation in the HPA‐Axis Gene NR3C2

et al. 2020

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Whole exome sequencing and copy‐number variant analysis was performed on a family with three brothers diagnosed with autism. Each of the siblings shares an alteration in the nuclear receptor subfamily 3 group C member 2 (NR3C2) gene that is predicted to result in a stop‐gain mutation (p.Q919X) in the mineralocorticoid receptor (MR) protein. This variant was maternally inherited and provides further evidence for a connection between the NR3C2 and autism. Interestingly, the NR3C2 gene encodes the MR protein, a steroid hormone‐regulated transcription factor that acts in the hypothalamic–pituitary–adrenal axis and has been connected to stress and anxiety, both of which are features often seen in individuals with autism. Autism Res 2020, 13: 523–531. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary Given the complexity of the genetics underlying autism, each gene contributes to risk in a relatively small number of individuals, typically less than 1% of all autism cases. Whole exome sequencing of three brothers with autism identified a rare variant in the nuclear receptor subfamily 3 group C member 2 gene that is predicted to strongly interfere with its normal function. This gene encodes the mineralocorticoid receptor protein, which plays a role in how the body responds to stress and anxiety, features that are often elevated in people diagnosed with autism. This study adds further support to the relevance of this gene as a risk factor for autism.

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Sleep phenotype of individuals with autism spectrum disorder bearing mutations in the PER2 circadian rhythm gene

Hoang

Yuen

Howe

et al. 2021

American J of Med Genetics Pt A

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The Per family of genes functions as a primary circadian rhythm maintenance in the brain. Mutations in PER2 are associated with familial advanced sleep‐phase syndrome 1 (FASPS1), and recently suggested in delayed sleep phase syndrome and idiopathic hypersomnia. The detection of PER2 variants in individuals with autism spectrum disorder (ASD) and without reported sleep disorders, has suggested a role of circadian‐relevant genes in the pathophysiology of ASD. It remains unclear whether these individuals may have, in addition to ASD, an undiagnosed circadian rhythm sleep disorder. The MSSNG database was used to screen whole genome sequencing data of 5,102 individuals with ASD for putative mutations in PER2. Families identified were invited to complete sleep phenotyping consisting of a structured interview and two standardized sleep questionnaires: the Pittsburgh Sleep Quality Index and the Morningness‐Eveningness Questionnaire. From 5,102 individuals with ASD, two nonsense, one frameshift, and one de novo missense PER2 variants were identified (0.08%). Of these four, none had a diagnosed sleep disorder. Three reported either a history of, or ongoing sleep disturbances, and one had symptoms highly suggestive of FASPS1 (as did a mutation carrier father without ASD). The individual with the missense variant did not report sleep concerns. The ASD and cognitive profiles of these individuals varied in severity and symptoms. The results support a possible role of PER2‐related circadian rhythm disturbances in the dysregulation of sleep overall and sometimes FASPS1. The relationship between dysregulated sleep and the pathophysiology of ASD require further exploration.

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Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks

Cited by 366 publications

References 111 publications

Brain gene co-expression networks link complement signaling with convergent synaptic pathology in schizophrenia

Brain gene co-expression networks link complement signaling with convergent synaptic pathology in schizophrenia

Three Brothers With Autism Carry a Stop‐Gain Mutation in the HPA‐Axis Gene NR3C2

Sleep phenotype of individuals with autism spectrum disorder bearing mutations in the PER2 circadian rhythm gene

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