Genome‐wide association analysis of autism identified multiple loci that have been reported as strong signals for neuropsychiatric disorders

Abstract

Autism is a common neurodevelopmental disorder with a moderate to a high degree of heritability, but only a few common genetic variants that explain the heritability have been associated. We performed a genome‐wide transmission disequilibrium test analysis of a newly genotyped autism case–parent triad samples (127 trios) in Han Chinese, identified top association signals at multiple single nucleotide polymorphisms (SNPs), including rs9839376 (OR = 2.59, P = 1.27 × 10−05) at KCNMB2, rs6044680 (OR = 0.319, P = 4.82 × 10−05) and rs7274133 (OR = 0.313, P = 3.22 × 10−05) at PCSK2, and rs310619 (OR = 2.40, P = 7.44 × 10−05) at EEF1A2. Furthermore, a genome‐wide combined P‐value of individual SNPs in two independent case–parent triad samples (total 402 triads, n = 1,206) identified SNPs at EGFLAM, ZDHHC2, AGBL1, and SNX29 as additional association signals for autism. While none of these signals achieved a genome‐wide significance in the two samples of our study, they have been reported in a previous genome‐wide association study of neuropsychiatric disorders, and the majority of these SNP have a significant cis‐regulatory association with mRNA in human tissues (false discovery rate (FDR) < 0.05). Our study warrants further study or replication with additional sample for association with autism and other neuropsychiatric disorders. Autism Res 2020, 13: 382–396. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary Autism is a common neurodevelopmental disorder, heritable, but only a few common genetic variants that explain the heritability have been associated. We conducted a genome‐wide association study with two cohorts of autism case–parent triad samples in Han Chinese and identified multiple single nucleotide polymorphisms that were reported as strong association signals in a previous genome‐wide association study of other neuropsychiatric disorders or related traits. Our study provides evidence for shared genetic variants among autism and other neuropsychiatric disorders.

Insulinopathies of the brain? Genetic overlap between somatic insulin-related and neuropsychiatric disorders

“…Although further studies will be needed to disentangle the biological meaning of these findings, we could speculate that the observed pathway-level negative genetic correlation between ASD and MetS/T2DM might reflect higher complexity of reciprocal regulation between monoamine and insulin signalling at the CNS and peripheral level (12). Interestingly, while the insulin processing pathway is generally involved in the generation and subsequent exocytosis of insulin-containing granules, individual genes within this set (i.e., syntaxin-1A (STX1A), vesicle-associated membrane protein 2/synaptobrevin-2 (VAMP2), proprotein convertase subtilisin/kexin type 2 (PCSK2)) have also been linked to presynaptic neurotransmission and previously been associated with autism, intellectual and neurodevelopmental disabilities (27, 28).…”

Network analysis of core and associated symptoms in preschool children with autism spectrum disorder

“…High comorbidity rates of ADHD were observed across ASD [32]. An increasing amount of evidence suggests that ASD and ADHD may have shared genetic risk patterns [33][34][35][36]. Family-based studies show that siblings of patients with ADHD have an increased risk of developing ASD symptoms [34], while studies of twins show that common genetic factors may explain 50% to 70% of the covariance between ASD and ADHD symptoms [35,37].…”

Effect of an autism-associated KCNMB2 variant, G124R, on BK channel properties

“…Thus, both accessory subunits are able to reduce the BK channel activity through different mechanisms, leading to multiple possibilities for alteration of neuronal excitability. While only β4 function is implicated in ASD-related learning disability at present, genome-wide association studies have recently identified KCNMB2 SNP associations in autism case trios and other neuropathological states ( Beecham et al, 2014 ; Kimbrel et al, 2018 ; Xia et al, 2020 ). β2 expression has been detected in several areas of the brain implicated in ASD ( Brenner et al, 2000b ; Nordahl et al, 2012 ; Schumann et al, 2004 ; Stoodley, 2014 ).…”