Interaction-integrated linear mixed model reveals 3D-genetic basis underlying Autism

Qing Li; Deshan Perera; Chen Cao; Jingni He; Jiayi Bian; Xingyu Chen; Feeha Azeem; Aaron Howe; Billie Au; Jingjing Wu; Jun Yan; Quan Long

doi:10.1016/j.ygeno.2023.110575

Interaction-integrated linear mixed model reveals 3D-genetic basis underlying Autism

Genomics. 2023 Mar;115(2):110575. doi: 10.1016/j.ygeno.2023.110575. Epub 2023 Feb 8.

Authors

Qing Li¹, Deshan Perera¹, Chen Cao¹, Jingni He¹, Jiayi Bian², Xingyu Chen¹, Feeha Azeem¹, Aaron Howe³, Billie Au⁴, Jingjing Wu², Jun Yan⁵, Quan Long⁶

Affiliations

¹ Department of Biochemistry and Molecular Biology, University of Calgary, Alberta T2N 1N4, Canada.
² Department of Mathematics and Statistics, University of Calgary, Alberta T2N 1N4, Canada.
³ Heritage Youth Researcher Summer Program, University of Calgary, Alberta T2N 1N4, Canada.
⁴ Department of Medical Genetics, University of Calgary, Alberta T2N 1N4, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Alberta T2N 1N4, Canada.
⁵ Department of Physiology and Pharmacology, University of Calgary, Alberta T2N 1N4, Canada; Hotchkiss Brain Institute, University of Calgary, Alberta T2N 1N4, Canada. Electronic address: juyan@ucalgary.ca.
⁶ Department of Biochemistry and Molecular Biology, University of Calgary, Alberta T2N 1N4, Canada; Department of Medical Genetics, University of Calgary, Alberta T2N 1N4, Canada; Department of Mathematics and Statistics, University of Calgary, Alberta T2N 1N4, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Alberta T2N 1N4, Canada; Hotchkiss Brain Institute, University of Calgary, Alberta T2N 1N4, Canada. Electronic address: quan.long@ucalgary.ca.

PMID: 36758877
DOI: 10.1016/j.ygeno.2023.110575

Abstract

Genetic interactions play critical roles in genotype-phenotype associations. We developed a novel interaction-integrated linear mixed model (ILMM) that integrates a priori knowledge into linear mixed models. ILMM enables statistical integration of genetic interactions upfront and overcomes the problems of searching for combinations. To demonstrate its utility, with 3D genomic interactions (assessed by Hi-C experiments) as a priori, we applied ILMM to whole-genome sequencing data for Autism Spectrum Disorders (ASD) and brain transcriptome data, revealing the 3D-genetic basis of ASD and 3D-expression quantitative loci (3D-eQTLs) for brain tissues. Notably, we reported a potential mechanism involving distal regulation between FOXP2 and DNMT3A, conferring the risk of ASD.

Keywords: 3D genomic interactions; Autism spectrum disorder; Genetic interaction; Genotype-phenotype association mapping; Linear mixed model.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Autism Spectrum Disorder* / genetics
Autistic Disorder* / genetics
Brain
Genetic Predisposition to Disease
Genomics
Humans
Whole Genome Sequencing

Substances

FOXP2 protein, human
DNMT3A protein, human