Journal Article

Exploring autism spectrum disorder and co-occurring trait associations to elucidate multivariate genetic mechanisms and insights

Salenius, Karoliina, Väljä, Niina, Lin, Jake, Ladd-Acosta, Christine, Thusberg, Sini, Fasano, Alessio, Iris, Francois, Roos, Christophe, Nykter, Matti, Autio, Reija

2024

Overview

Background Autism spectrum disorder (ASD) is a partially heritable neurodevelopmental trait, and people with ASD may also have other co-occurring trait such as ADHD, anxiety disorders, depression, mental health issues, learning difficulty, physical health traits and communication challenges. The concomitant development of ASD and other neurological traits is assumed to result from a complex interplay between genetics and the environment. However, only a limited number of studies have performed multivariate genome-wide association studies (GWAS) for ASD. Methods We conducted to-date the largest multivariate GWAS on ASD and 8 ASD co-occurring traits (ADHD, ADHD childhood, anxiety stress (ASDR), bipolar (BIP), disruptive behaviour (DBD), educational attainment (EA), major depression, and schizophrenia (SCZ)) using summary statistics from leading studies. Multivariate associations and central traits were further identified. Subsequently, colocalization and Mendelian randomization (MR) analysis were performed on the associations identified with the central traits containing ASD. To further validate our findings, pathway and quantified trait loci (QTL) resources as well as independent datasets consisting of 112 (45 probands) whole genome sequence data from the GEMMA project were utilized. Results Multivariate GWAS resulted in 637 significant associations ( p  < 5e-8), among which 322 are reported for the first time for any trait. 37 SNPs were identified to contain ASD and one or more traits in their central trait set, including variants mapped to known SFARI ASD genes MAPT , CADPS and NEGR1 as well as novel ASD genes KANSL1 , NSF and NTM , associated with immune response, synaptic transmission, and neurite growth respectively. Mendelian randomization analyses found that genetic liability for ADHD childhood, ASRD and DBT has causal effects on the risk of ASD while genetic liability for ASD has causal effects on the risk of ADHD, ADHD childhood, BIP, WA, MDD and SCZ. Frequency differences of SNPs found in NTM and CADPS genes, respectively associated with neurite growth and neural/endocrine calcium regulation, were found between GEMMA ASD probands and controls. Pathway, QTL and cell type enrichment implicated microbiome, enteric inflammation, and central nervous system enrichments. Conclusions Our study, combining multivariate GWAS with systematic decomposition, identified novel genetic associations related to ASD and ASD co-occurring driver traits. Statistical tests were applied to discern evidence for shared and interpretable liability between ASD and co-occurring traits. These findings expand upon the current understanding of the complex genetics regulating ASD and reveal insights of neuronal brain disruptions potentially driving development and manifestation. Highlights Multivariate GWAS resulted in 637 significant ASD associations ( p  < 5e-8), among which 322 are reported for the first time. The novel associations mapped to known SFARI ASD genes CADPS , MAPT and NEGR1 and novel ASD genes KANSL1 , NSF and NTM , associated with immune response, synaptic transmission, and neurite growth, potentially driving the gut brain-barrier hypothesis underpinning ASD development. CuONPs induce co-occurrence of autophagy activation and autophagic flux blockade. Mendelian randomization analyses found that genetic liability for ASRD and DBT have causal effects on the risk of ASD while genetic liability for ASD have causal effects on the risk of ADHD, BIP, WA, MDD and SCZ. Bidirectional genetic liability causal effects were confirmed between ASD and ADHD childhood.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Anxiety / Anxiety disorders / ASD / ASD genetically correlated traits / Attention Deficit Disorder with Hyperactivity - genetics / Attention deficit hyperactivity disorder / Autism / Autism Spectrum Disorder - genetics / Autistic children / Central nervous system / Child & adolescent mental health / Children / Comorbidity / Decomposition / Development and progression / Enteric nervous system / Epilepsy / GEMMA / Gene frequency / Gene regulation / Genes / Genetic analysis / Genetic aspects / Genetic Predisposition to Disease - genetics / Genome-wide association studies / Genome-Wide Association Study / Genomes / Genomics / Humans / Immune response / Liability / Medicine / Medicine & Public Health / Mendelian randomization / Mendelian Randomization Analysis / Mental depression / Mental disorders / Mental illness / Microbiomes / Multivariate GWAS / Neurodevelopmental disorders / Nucleotide sequence / Obsessive compulsive disorder / Pervasive developmental disorders / Polymorphism, Single Nucleotide - genetics / Psychiatry / Psychotherapy / Quantitative trait loci / Quantitative Trait Loci - genetics / Schizophrenia / Single-nucleotide polymorphism / Software / Statistical analysis / Stress / Synaptic transmission