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. 2024 Dec 18;24(1):934.
doi: 10.1186/s12888-024-06392-w.

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

Karoliina Salenius #  1 , Niina Väljä #  1 , Sini Thusberg  1 , Francois Iris  2 , Christine Ladd-Acosta  3 , Christophe Roos  4 , Matti Nykter  1   5 , Alessio Fasano  6   7 , Reija Autio #  8 , Jake Lin #  9   10 ; GEMMA study
Affiliations

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

Karoliina Salenius et al. BMC Psychiatry. .

Abstract

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.

Keywords: ASD; ASD genetically correlated traits; GEMMA; Mendelian randomization; Multivariate GWAS.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: The GEMMA study was approved by the relevant ethics committee of each enrolling country. Particularly, CE Campania Sud (IRB n.30/2019) for Italy; Partners Human Research (IRB ver.01/04/2019) for USA; and Clinical Research Ethics Committee of Galway University Hospital (IRB n. C.A. 2127/19) for Ireland. A written consent form will be signed by each participant or their legal representative. Consent for publication: Consent, relevant to GEMMA subjects, is granted and signed by each participant or their legal representative. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Workflow for the analyses conducted in the study. Multivariate GWAS was performed on selected GWAS studies including ASD and 8 co-occurring traits: ADHD, ADHD childhood, bipolar, anxiety, disruptive behaviour, educational attainment, major depression and schizophrenia. 37 SNPs were selected and evaluated with Colocalization and Mendelian Randomization. Further validation of these SNPs utilized pathway and EBI eQTL/sQTL catalogs as well as the GEMMA -study. The GEMMA whole genome sequencing (WGS) processing included variant calling to infer structural and single nucleotide variants (SVs and SNVs) present in the samples
Fig. 2
Fig. 2
Results from the post GWAS analysis of the 37 selected SNPs. a,b) Colocalization processing using the original summary statistics of ASD and EA for (a) rs62061734 (MAPT, failed colocalization with H4 probability 8.19%, p = 0.09), ASD and NSF for (b) rs538628 (NSF, SCZ passed colocalization with H4 probability 94%, p = 1.1e-05), depicting supporting regional SNPs (x-axis) and their negative log10 p-value (y-axis) and effect direction (circles negative, triangles positive). c,d) Mendelian randomization (MR) results using inverse variance weighted (IVW) -method for association of ASD SNP effects (y-axis) and c) EA and d) SCZ effects (x-axis). e) Pathway analysis for the genes associated with the selected SNPs shows enrichment in processes related to neurons using Reactome database. The length of the bar represents the significance of that specific gene-set or pathway and the color indicates the significance of the pathway. Details of the pathways and genes with their associated p-values are listed in Supplementary Table 8. f) Organ system enrichment was applied using WebCSEA, using the selected 37 multivariate gene associations and found enrichment (p < 1e-03) with the ASD relevant digestive, nervous and sensory organ systems as well as lymphatic and respiratory systems
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