Estimating the Prevalence and Genetic Risk Mechanisms of ARFID in a Large Autism Cohort

Abstract

This study is the first genetically-informed investigation of avoidant/restrictive food intake disorder (ARFID), an eating disorder that profoundly impacts quality of life for those affected. ARFID is highly comorbid with autism, and we provide the first estimate of its prevalence in a large and phenotypically diverse autism cohort (a subsample of the SPARK study, N = 5,157 probands). This estimate, 21% (at a balanced accuracy 80%), is at the upper end of previous estimates from studies based on clinical samples, suggesting under-diagnosis and potentially lack of awareness among caretakers and clinicians. Although some studies suggest a decrease of disordered eating symptoms by age 6, our estimates indicate that up to 17% (at a balanced accuracy 87%) of parents of autistic children are also at heightened risk for ARFID, suggesting a lifelong risk for disordered eating. We were also able to provide the first estimates of narrow-sense heritability (h2) for ARFID risk, at 0.45. Genome-wide association revealed a single hit near ZSWIM6, a gene previously implicated in neurodevelopmental conditions. While, the current sample was not well-powered for GWAS, effect size and heritability estimates allowed us to project the sample sizes necessary to more robustly discover ARFID-linked loci via common variants. Further genetic analysis using polygenic risk scores (PRS) affirmed genetic links to autism as well as neuroticism and metabolic syndrome.

Feeding Problems Including Avoidant Restrictive Food Intake Disorder in Young Children With Autism Spectrum Disorder in a Multiethnic Population

“…Although our study group from a multiethnic lowresource area was small and might not be representative for all children with ASD, together with earlier research reporting frequent feeding problems in children with ASD (1, 2) and the experiences from clinicians in the field, our results indicate that ARFID is a common coexisting problem in children with ASD. Another current study also highlights the high comorbidity of ARFID in ASD with an estimated ARFID prevalence of 21% based on parent questionnaires from a large autism cohort (64).…”

How genetic analysis may contribute to the understanding of avoidant/restrictive food intake disorder (ARFID)

“…While ASD and ARFID frequently co-occur (as described above), far from all people with ARFID have ASD, limiting the generalizability of the results in this ASD group to the whole population with ARFID. The authors present a moderate, small nucleotide polymorphism (SNP)-based heritability of a continuous ARFID risk score, comparable to estimates in other EDs [ 55 ], but with relatively large confidence intervals (CIs; 0.45, 95% CI 0.13–0.76) [ 54 ]. Although the authors of this study acknowledge it was likely underpowered for gene discovery, one SNP on chromosome 5 did reach genome wide significance.…”

“…Based on the findings of Koomar et al [ 54 ] and the twin/family study data of related phenotypes above, it is reasonable to expect that the ARFID phenotype(s) will be at least moderately heritable, and that the degree of heritability and nature of the underlying genetic variants may differ across ARFID presentations.…”

“…The roots of psychiatric genetics lie in family and twin studies that provide the first evidence that a disorder or condition aggregates in families, and can quantify the relative contribution of genetics, and shared or unique environment. No family or twin studies of ARFID have yet been published, and although there is one genetically-informed investigation of ARFID [ 54 ], this was performed with a sample of 3142 genotyped probands with ASD, of whom < 20% were classed as high-risk for ARFID. While ASD and ARFID frequently co-occur (as described above), far from all people with ARFID have ASD, limiting the generalizability of the results in this ASD group to the whole population with ARFID.…”

“…A significant challenge in GWAS is achieving sufficient statistical power given the generally small effect sizes of the loci sought, which requires genotyping and phenotyping of large numbers of cases and controls. A projection by Koomar et al [ 54 ] suggests the number of participants required to achieve sufficient power for further ARFID gene discovery to be n = 10,000. Meta-analysis has proven a powerful tool for enhancing the power of individual GWAS discovery datasets, and identifying increasing numbers of genetic risk variants.…”