Multi-trait analysis for genome-wide association study of five psychiatric disorders

Wu, Ye; Cao, Hongbao; Baranova, Ancha; Huang, Hailiang; Li, Sheng; Cai, Lei; Rao, Shuquan; Dai, Minhan; Xie, Min; Dou, Yikai; Hao, Qinjian; Zhu, Ling; Zhang, Xiangrong; Yao, Yin; Zhang, Fuquan; Xu, Mingqing; Wang, Qiang

doi:10.1038/s41398-020-00902-6

Cited by 165 publications

(124 citation statements)

References 65 publications

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“…As one of the validation criteria, relative risk estimates should have been reported with standard errors or 95% CIs. Data are then extracted from the validated articles [ 40 , 41 ]. Dosage effect and age or gender specificity should be considered when evaluating the response to NTP treatment.…”

Section: Discussionmentioning

confidence: 99%

Association of NAT2 genetic polymorphism with the efficacy of Neurotropin® for the enhancement of aggrecan gene expression in nucleus pulposus cells: a pilot study

et al. 2021

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Background Intervertebral disc degeneration, one of the major causes of low-back pain, results from altered biosynthesis/turnover of extracellular matrix in the disc. Previously, we reported that the analgesic drug Neurotropin® (NTP) had an anabolic effect on glycosaminoglycan synthesis in cultured nucleus pulposus (NP) cells via the stimulation of chondroitin sulfate N-acetylgalactosaminyltransferase 1. However, its effect on the aggrecan core protein was not significantly detected, because of the data variance. A microarray analysis suggested that the effect of NTP on aggrecan was correlated with N-acetyltransferase 2 (NAT2), a drug-metabolizing enzyme. Specific NAT2 alleles are known to correlate with rapid, intermediate, and slow acetylation activities and side effects of various drugs. We investigated the association between the efficacy of NTP on aggrecan expression and the NAT2 genotype in cell donors. Methods NP cells were isolated from intervertebral disc tissues donated by 31 Japanese patients (28–68 years) who underwent discectomy. NTP was added to the primary cell cultures and its effect on the aggrecan mRNA was analyzed using real-time quantitative PCR. To assess acetylator status, genotyping was performed based on the inferred NAT2 haplotypes of five common single-nucleotide polymorphisms using allele-specific PCR. Results The phenotype frequencies of NAT2 in the patients were 0%, 42.0%, and 58.0% for slow, intermediate, and rapid acetylators, respectively. The proportions of responders to NTP treatment (aggrecan upregulation, ≥ 1.1-fold) in the intermediate and rapid acetylators were 76.9% and 38.9%, respectively. The odds ratio of the comparison of the intermediate acetylator status between responders and nonresponders was 5.2 (95% CI 1.06–26.0, P = 0.036), and regarding the 19 male patients, this was 14.0 (95% CI 1.54–127.2, P = 0.012). In the 12 females, the effect was not correlated with NAT2 phenotype but seemed to become weaker along with aging. Conclusions An intermediate acetylator status significantly favored the efficacy of NTP treatment to enhance aggrecan production in NP cells. In males, this tendency was detected with higher significance. This study provides suggestive data of the association between NAT2 variants and the efficacy of NTP treatment. Given the small sample size, results should be further confirmed.

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Section: Discussionmentioning

confidence: 99%

Association of NAT2 genetic polymorphism with the efficacy of Neurotropin® for the enhancement of aggrecan gene expression in nucleus pulposus cells: a pilot study

et al. 2021

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“…), was used to identify cholinergic-relevant gene sets encompassing a total of 345 genes, which constituted the cholinergic activity gene set for this ontological enrichment analysis. An autism gene set containing 47 genes from a recent cross-trait genome-wide meta-analysis (Wu et al, 2020) was used because it identified more risk genes for ASD compared with another GWAS study for ASD, thus providing enhanced statistical power for the present study (Grove et al, 2019).…”

Section: Identification Of Ontologies Associated With Each Gene Set mentioning

confidence: 99%

“…Each instance of a relationship identified by NLPbased word triplet identification was graded by Pathway Studio in terms of confidence levels of 1-3, with a maximum confidence level of 3 being defined as an entity-to-entity relationship supported by at least three peer reviewed publications reflected FIGURE 1 | Gene ontology overlap between autism and cholinergic metabolism gene sets. Overlap between an autism-associated genome-wide associated studies gene set (Wu et al, 2020) and cholinergic pathways gene set (MSigDB v7.1) was identified using Venny 2.1. The two shared ontologies were (1) regulation of ion transport and (2) positive regulation of ion transport, identifying ion transport functionality as a critical area of enrichment for further analysis.…”

Section: Gene Set Pathway Intersection Analysis Of Shared Ontologiesmentioning

confidence: 99%

“…While the (rs740883) SNP-related differences in predicted splicing patterns of GABBR1 were minimal, the KCNN2 variant rs13188074 yielded a high confidence prediction of a lowered strength within the splice site between the seventh and FIGURE 5 | GABBR1 may influence acetylcholinesterase regulation. GABBR1 is an autism-associated gene that codes for a membrane-bound protein (GABA B1 ) (Wu et al, 2020). The binding of the neurotransmitter GABA to GABA B1 has several implications for cholinergic signaling, sensory signal transduction, and ion transport, across multiple cascades.…”

Section: Supportive Evidence For Kcnn2 Variant As a Modifier Of Splicingmentioning

confidence: 99%

“…The autism GWAS dataset is available as a supplementary file for the original article (Wu et al, 2020).…”

Section: Data Availability Statementmentioning

confidence: 99%

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In silico Gene Set and Pathway Enrichment Analyses Highlight Involvement of Ion Transport in Cholinergic Pathways in Autism: Rationale for Nutritional Intervention

et al. 2021

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Food is the primary human source of choline, an essential precursor to the neurotransmitter acetylcholine, which has a central role in signaling pathways that govern sensorimotor functions. Most Americans do not consume their recommended amount of dietary choline, and populations with neurodevelopmental conditions like autism spectrum disorder (ASD) may be particularly vulnerable to consequences of choline deficiency. This study aimed to identify a relationship between ASD and cholinergic signaling through gene set enrichment analysis and interrogation of existing database evidence to produce a systems biology model. In gene set enrichment analysis, two gene ontologies were identified as overlapping for autism-related and for cholinergic pathways-related functions, both involving ion transport regulation. Subsequent modeling of ion transport intensive cholinergic signaling pathways highlighted the importance of two genes with autism-associated variants: GABBR1, which codes for the gamma aminobutyric acid receptor (GABAB1), and KCNN2, which codes for calcium-activated, potassium ion transporting SK2 channels responsible for membrane repolarization after cholinergic binding/signal transmission events. Cholinergic signal transmission pathways related to these proteins were examined in the Pathway Studio environment. The ion transport ontological associations indicated feasibility of a dietary choline support as a low-risk therapeutic intervention capable of modulating cholinergic sensory signaling in autism. Further research at the intersection of dietary status and sensory function in autism is warranted.

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Autism Spectrum Disorder

Hirota

King

2023

JAMA

257

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ImportanceAutism spectrum disorder (ASD), characterized by deficits in social communication and the presence of restricted, repetitive behaviors or interests, is a neurodevelopmental disorder affecting approximately 2.3% children aged 8 years in the US and approximately 2.2% of adults. This review summarizes evidence on the diagnosis and treatment of ASD.ObservationsThe estimated prevalence of ASD has been increasing in the US, from 1.1% in 2008 to 2.3% in 2018, which is likely associated with changes in diagnostic criteria, improved performance of screening and diagnostic tools, and increased public awareness. No biomarkers specific to the diagnosis of ASD have been identified. Common early signs and symptoms of ASD in a child’s first 2 years of life include no response to name when called, no or limited use of gestures in communication, and lack of imaginative play. The criterion standard for the diagnosis of ASD is a comprehensive evaluation with a multidisciplinary team of clinicians and is based on semistructured direct observation of the child’s behavior and semistructured caregiver interview focused on the individual’s development and behaviors using standardized measures, such as the Autism Diagnostic Observation Schedule-Second Edition and the Autism Diagnostic Interview. These diagnostic measures have sensitivity of 91% and 80% and specificity of 76% and 72%, respectively. Compared with people without ASD, individuals with ASD have higher rates of depression (20% vs 7%), anxiety (11% vs 5%), sleep difficulties (13% vs 5%), and epilepsy (21% with co-occurring intellectual disability vs 0.8%). Intensive behavioral interventions, such as the Early Start Denver Model, are beneficial in children 5 years or younger for improvement in language, play, and social communication (small to medium effect size based on standardized mean difference). Pharmacotherapy is indicated for co-occurring psychiatric conditions, such as emotion dysregulation or attention-deficit/hyperactivity disorder. Risperidone and aripiprazole can improve irritability and aggression (standardized mean difference of 1.1, consistent with a large effect size) compared with placebo. Psychostimulants are effective for attention-deficit/hyperactivity disorder (standardized mean difference of 0.6, consistent with a moderate effect size) compared with placebo. These medications are associated with adverse effects including, most commonly, changes in appetite, weight, and sleep.Conclusions and RelevanceASD affects approximately 2.3% of children aged 8 years and approximately 2.2% of adults in the US. First-line therapy consists of behavioral interventions, while co-occurring psychiatric conditions, such as anxiety or aggression, may be treated with specific behavioral therapy or medication.

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Multi-trait analysis for genome-wide association study of five psychiatric disorders

Cited by 165 publications

References 65 publications

Association of NAT2 genetic polymorphism with the efficacy of Neurotropin® for the enhancement of aggrecan gene expression in nucleus pulposus cells: a pilot study

Association of NAT2 genetic polymorphism with the efficacy of Neurotropin® for the enhancement of aggrecan gene expression in nucleus pulposus cells: a pilot study

In silico Gene Set and Pathway Enrichment Analyses Highlight Involvement of Ion Transport in Cholinergic Pathways in Autism: Rationale for Nutritional Intervention

Autism Spectrum Disorder

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