T24. UNCOVERING EATING DISORDER GENETICS THROUGH LARGE SCALE SEQUENCING

• Published in: European neuropsychopharmacology Vol. 87; pp. 168 - 169
• Main Authors: Ivankovic, Franjo, Javaras, Kristin N, Pennels, Kaitlin, Stevens, Christine, Stroud, Rocky, Jennings, Faith, Daly, Mark, Neale, Benjamin
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01-10-2024
• ISSN: 0924-977X
• DOI: 10.1016/j.euroneuro.2024.08.334

Both anorexia (AN) and bulimia (BN) nervosa are marked by a substantial genetic component, with family study heritability estimates of 0.58-0.76 for AN and 0.30-0.83 for BN. Despite the heritability estimates, discovery of genetic risk factors for AN and BN remain limited. Genome-wide association studies are limited in power and resolution, and discoverability of genetic risk factors is hindered by study-design limitations such as potential confounding by BMI due to current AN nosology.
Our analysis is focusing on existing samples from large biobanks (FinnGen, N=4,616; All of Us, N=2,500; MGB biobank, N=1,000), representing one of the largest collective cohorts in eating disorder genome sequencing so far. We are additionally planning to sequence additional 10,000 AN/BN cases and 10,000 controls over the next 2 years, recruited in the clinics across the United States, Mexico, and Europe, as well as direct-to-participant (DTP) recruitment in the United States. PRS analyses using the previous AN GWAS have been performed to assess eating disorder phenotypes in existing FinnGen (N≈500,000) and All of Us (N≈250,00) genotyping data. Models including age, sex, and/or BMI have also been examined. To facilitate assessment of DTP participants, we have developed the McLean-Stanford-Washington Eating Disorder (MSWED) questionnaire, a screening tool to identify lifetime diagnosis of eating disorders, which was initially validated in the Mexican clinically-ascertained cohorts (N=350) and is undergoing validation against SCID-5 in the United States.
We have identified over 20,900 samples for sequencing, which include planned sequencing of 4,000 samples in the DTP arm. About 2,300 samples are currently being processed through the sequencing pipeline. PRS analysis has shown that previous AN GWAS may predict ED case status, but the majority of predictive power is driven by age, sex, and BMI. Additionally, we have identified 479 individuals with AN and/or BN for immediate rare variant analysis in the All of Us (v7) cohort. Preliminary validation of MSWED resulted in high specificity (AN=0.93, BN=0.97) and lower sensitivity (AN=0.72, BN=0.51), as intended.
Initial analyses of common and rare variants in cohorts where sequencing data are available are underway. We are expanding these cohorts with recruitment and genome sequencing of additional samples from ancestrally diverse, clinically recruited and community-based participants. Initial MSWED validation suggests that it is highly specific, making it a valuable tool for identification of eating disorder cases for genetic research in community-based participants. Our long-term goal is to leverage genome sequencing in diverse populations to uncover rare and common variants involved in eating disorder pathobiology.
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