Exploring autism and autism co-occurring condition associations to elucidate multivariate genetic mechanisms and insights

Abstract

AbstractBackgroundGenome-wide association (GWAS) and large scaled exome based studies have successfully uncovered hundreds of associations and genes related to autism. Autism is a partially heritable neurodevelopmental condition. Autistic people may also have other co-occurring conditions such as ADHD, anxiety disorders, depression, mental health issues, learning difficulty, physical health conditions and communication challenges. The concomitant development of autism and other neurological conditions is assumed to result from a complex interplay between genetics and the environment. However, only a limited number of studies have performed multivariate genetic autism association studies.MethodsWe conducted the largest multivariate GWAS with autism and 11 autism co-occurring traits (ADHD, ADHD child, anxiety, IBS, depression, digestion disorders, education attainment, epilepsy, panic, social phobia) using summary statistics from leading reputable consortiums: iPSYCH, PGC, 23andMe and UK Biobank. 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 autism. To further validate our findings we utilized independent datasets consisting of 35,584 exome sequence iPSYCH data and 53 (13 probands) Whole Genome Sequence from the GEMMA project.ResultsMultivariate GWAS resulted in 380 significant associations (p-value < 5e-8), among which 203 are reported for the first time for any trait. 22 SNPs were identified to contain autism and one or more comorbidities in their central trait set, including variants mapped to known SFARI autism genes such as MAPT and NEGR1. NSF, a serotonin receptor binding gene, was found to be associated with autism with education attainment. Mendelian randomization and colocalization analyses found that education attainment, ADHD and ADHD childhood are liable traits toward autism. Additionally, allele proportions and distribution differences between MAPT (17q21.31) region aberrations and MAPT H1/H2 haplotypes, known to associate with neurodevelopment, and the reported autism-central SNPs were found within GEMMA autism probands and controls. Pathway and gene card analysis also implicated microbiome, enteric inflammation, and central nervous system enrichments.ConclusionsOur study combined multivariate genome-wide association testing with systematic decomposition to identify novel genetic associations related to autism and autism co-occurring driver traits. Statistical tests were applied to discern evidence for shared and interpretable liability between autism and co-occurring traits. We additionally detected differences in the SNP association frequency patterns between autism probands and familial controls in an independent validation cohort. These findings contribute to our understanding of the complex genetic underpinnings of autism and provide valuable insights into its potential driver traits and genetic markers.