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

Abstract

BackgroundAutism is a partially heritable neurodevelopmental condition, and people with autism 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 analysis on multivariate genetic autism associations. MethodsWe conducted to-date the largest multivariate GWAS on autism and 8 autism co-occurring condition traits (ADHD, ADHD childhood, anxiety stress, bipolar, disruptive behaviour, educational attainment, major depression, and schizophrenia) 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 autism. To further validate our findings, pathway and quantified trait loci (QTL) resources as well as independent datasets consisting of 92 (30 probands) whole genome sequence data from the GEMMA project were utilized. ResultsMultivariate 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 autism and one or more traits in their central trait set, including variants mapped to known SFARI autism genes MAPT 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 all 8 co-occuring conditions are associated with autism while colocalization provided strong evidence of shared genetic aetiology between autism and education attainment, schizophrenia and bipolar traits. Allele proportions differences between MAPT (17q21.31) region aberrations and MAPT H1/H2 haplotypes, known to associate with neurodevelopment wwere found between GEMMA autism probands and controls. Pathway, QTL and cell type enrichment implicated microbiome, enteric inflammation, and central nervous system enrichments. ConclusionsOur study, combining multivariate genome-wide association testing with systematic decomposition identified 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. These findings expand upon the current understanding of the complex genetics regulating autism and reveal insights of neuronal brain disruptions potentially driving development and manifestation. HighlightsO_LIMultivariate GWAS resulted in 637 significant ASD associations (p < 5e-8), among which 322 are reported for the first time. C_LIO_LIThe novel associations mapped to known SFARI autism genes MAPT and NEGR1 and novel ASD markers KANSL1, NSF and NTM markers, associated with immune response, synaptic transmission, and neurite growth, potentially driving the gut brain-barrier hypothesis driving ASD. C_LIO_LIMendelian randomization analyses found that the co-occuring traits ADHD, ADHD childhood, anxiety stress, bipolar, disruptive behaviour, educational attainment, major depression, and schizophrenia are strongly associated with autism. C_LI