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.

Keywords: ARFID; autism; eating disorders; genetics; heritability.

Figure 1

The association of individual age-corrected and scaled items from the parent or proband surveys, quantified as the median difference (location shift) from a Wilcox rank-sum test. All items were scaled to have a unit variance of 1 prior to quantification. Items marked with an asterisk (*) were included in the ARFID Score model.

Figure 2

The association of various assessments from the probands with the NIAS factors and ARFID Score, quantified as Spearman correlation coefficient. For differences for those identified as high risk for ARFID (ARFID Risk Group), the association is quantified as the median difference (location shift) from a Wilcox rank-sum test.

Figure 3

Spearman correlation coefficients for ARFID Score and NIAS factors with PRS for a variety of neuropsychiatric and morphological traits. The strongest association across three p-value thresholds (0.0005, 0.05, and 0.5), is shown here. FDR correction applied across all tests (n = 336). IBS, irritable bowel syndrome; IBD, inflammatory bowel disease; Scz, schizophrenia; BpD, bipolar disorder; ADHD, attention deficit hyperactivity disorder; MDD, major depression disorder; autism, autism; An, anorexia; MetS, metabolic syndrome; BW, birth weight; BMI, body mass index; BMR, basal metabolic rate; Neur, neuroticism; EduA, educational attainment.

Figure 4

(A) SNP-based (i.e., narrow sense) heritability estimates of ARFID Score and ARFID Risk Group (high vs. low), with 95% confidence intervals. (B) Excess pedigree heritablility estimates (beyond what is explained by SNP h²) ARFID Score and ARFID risk group, with 95% confidence intervals. (C) GWAS Manhattan plot of the proband ARFID Score. The dashed line indicates the genome-wide significance threshold of 5e⁻⁸.