Genome-wide association study and identification of chromosomal enhancer maps in multiple brain regions related to autism spectrum disorder

AbstractBackgroundAutism spectrum disorder (ASD) has phenotypically and genetically heterogeneous characteristics. A simulation study demonstrated that attempts to categorize patients with a complex disease into more homogeneous subgroups could have more power to elucidate hidden heritability.MethodsWe conducted cluster analyses using the k-means algorithm with a cluster number of 15 based on phenotypic variables from the Simons Simplex Collection (SSC). As a preliminary study, we conducted a conventional genome-wide association study (GWAS) with a dataset of 597 ASD cases and 370 controls. In the second step, we divided cases based on the clustering results and conducted GWAS in each of the subgroups vs controls (cluster-based GWAS). We also conducted cluster-based GWAS on another SSC dataset of 712 probands and 354 controls in the replication stage.ResultsIn the preliminary study, we observed no significant associations. In the second step of cluster-based GWASs, we identified 65 chromosomal loci, which included 30 intragenic loci located in 21 genes and 35 intergenic loci that satisfied the threshold of P<5.0×10−8. Some of these loci were located within or near previously reported candidate genes for ASD: CDH5, CNTN5, CNTNAP5, DNAH17, DPP10, DSCAM, FOXK1, GABBR2, GRIN2A5, ITPR1, NTM, SDK1, SNCA and SRRM4. Of these 65 significant chromosomal loci, rs11064685 located within the SRRM4 gene had a significantly different distribution in the cases vs. controls in the replication cohort.ConclusionsThese findings suggest that clustering may successfully identify subgroups with relatively homogeneous disease etiologies. Further cluster validation and replication studies are warranted in larger cohorts.

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Novel Insight Into the Etiology of Autism Spectrum Disorder Gained by Integrating Expression Data With Genome-wide Association Statistics

Biological Psychiatry ◽

10.1016/j.biopsych.2019.04.034 ◽

2019 ◽

Vol 86 (4) ◽

pp. 265-273 ◽

Cited By ~ 17

Author(s):

Oliver Pain ◽

Andrew J. Pocklington ◽

Peter A. Holmans ◽

Nicholas J. Bray ◽

Heath E. O’Brien ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Genome Wide Association ◽

Expression Data ◽

Genome Wide ◽

Insight Into

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Genome-Wide Association Studies of Copy Number Variation in Autism Spectrum Disorder

Autism - A Neurodevelopmental Journey from Genes to Behaviour ◽

10.5772/22207 ◽

2011 ◽

Author(s):

Hae-Jin Hu ◽

Yeun-Jun Chung

Keyword(s):

Autism Spectrum Disorder ◽

Copy Number Variation ◽

Copy Number ◽

Association Studies ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Number Variation

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Genome-wide association study of REM sleep behavior disorder identifies novel loci with distinct polygenic and brain expression effects

10.1101/2021.09.08.21254232 ◽

2021 ◽

Author(s):

Lynne Krohn ◽

Karl Heilbron ◽

Cornelis Blauwendraat ◽

Regina H. Reynolds ◽

Eric Yu ◽

...

Keyword(s):

Association Study ◽

Rem Sleep ◽

Genome Wide Association Study ◽

Genetic Risk Score ◽

Rem Sleep Behavior Disorder ◽

Behavior Disorder ◽

Brain Regions ◽

Genome Wide Association ◽

Sleep Behavior ◽

Genome Wide

ABSTRACTRapid eye movement (REM) sleep behavior disorder (RBD), enactment of dreams during REM sleep, is an early clinical symptom of alpha-synucleinopathies. RBD also defines more severe forms of alpha-synucleinopathies. The genetic background of RBD and its underlying mechanisms are not well understood. Here, we performed the first genome-wide association study of RBD, identifying five RBD risk loci. Expression analyses highlight SNCA-AS1 and SCARB2 differential expression in different brain regions in RBD, with SNCA-AS1 further supported by colocalization analyses. Genetic risk score and other analyses provide further insights into RBD genetics, highlighting RBD as a unique subpopulation that will allow future early intervention.

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Novel insights into the common heritable liability to addiction: a multivariate genome-wide association study

10.1101/2021.11.19.21266548 ◽

2021 ◽

Author(s):

Tabea Schoeler ◽

Jessie Baldwin ◽

Andrea Allegrini ◽

Wikus Barkhuizen ◽

Andrew McQuillin ◽

...

Keyword(s):

Association Study ◽

Genetic Architecture ◽

Genome Wide Association Study ◽

Genetic Correlations ◽

Brain Regions ◽

Genome Wide Association ◽

Drug Reinforcement ◽

Heroin Use ◽

Genome Wide ◽

The Common

Addiction to nicotine, alcohol and cannabis commonly co-occurs, which is thought to partly stem from a common heritable liability. To elucidate its genetic architecture, we modelled the common liability to addiction, inferred from genetic correlations among six measures of dependence and frequency of use of nicotine, alcohol and cannabis. Forty-two genetic variants were identified in the multivariate genome-wide association study on the common liability to addiction, of which 67% were novel and not associated with the six phenotypes. Mapped genes highlighted the role of dopamine (e.g., dopamine D2 gene), and showed enrichment for a several components of the central nervous systems (e.g., mesocorticolimbic brain regions) and molecular pathways (dopaminergic, glutamatergic, GABAergic) that are thought to modulate drug reinforcement. Genetic correlations with other traits were most prominent for reward-related behaviours (e.g., risk-taking, cocaine and heroin use) and mood (e.g., depression, insomnia). These genome-wide results triangulate and expand previous preclinical and human studies focusing on the neurobiological substrates of addiction, and help to elucidate the common genetic architecture underlying addiction.

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Epigenome-wide association study of narcolepsy-affected lateral hypothalamic brains, and overlapping DNA methylation profiles between narcolepsy and multiple sclerosis

SLEEP ◽

10.1093/sleep/zsz198 ◽

2019 ◽

Vol 43 (1) ◽

Cited By ~ 1

Author(s):

Mihoko Shimada ◽

Taku Miyagawa ◽

Akari Takeshima ◽

Akiyoshi Kakita ◽

Hiromi Toyoda ◽

...

Keyword(s):

Multiple Sclerosis ◽

Dna Methylation ◽

Association Study ◽

Genome Wide Association Study ◽

Basic Protein ◽

Temporal Cortex ◽

Brain Regions ◽

Genome Wide Association ◽

Genome Wide ◽

A Genome

Abstract Narcolepsy with cataplexy is a sleep disorder caused by a deficiency in hypocretin neurons in the lateral hypothalamus (LH). Here we performed an epigenome-wide association study (EWAS) of DNA methylation for narcolepsy and replication analyses using DNA samples extracted from two brain regions: LH (Cases: N = 4; Controls: N = 4) and temporal cortex (Cases: N = 7; Controls: N = 7). Seventy-seven differentially methylated regions (DMRs) were identified in the LH analysis, with the top association of a DMR in the myelin basic protein (MBP) region. Only five DMRs were detected in the temporal cortex analysis. Genes annotated to LH DMRs were significantly associated with pathways related to fatty acid response or metabolism. Two additional analyses applying the EWAS data were performed: (1) investigation of methylation profiles shared between narcolepsy and other disorders and (2) an integrative analysis of DNA methylation data and a genome-wide association study for narcolepsy. The results of the two approaches, which included significant overlap of methylated positions associated with narcolepsy and multiple sclerosis, indicated that the two diseases may partly share their pathogenesis. In conclusion, DNA methylation in LH where loss of orexin-producing neurons occurs may play a role in the pathophysiology of the disease.

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