ASD Biomarker MV GWAS (MetaPhat/MetaCCA)

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.
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.
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.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.