Scientific rationale:
Anorexia nervosa (AN) is a complex disorder influenced by genetic, environmental, and neurobiological factors. Polygenic risk scores (PRS) have been identified for AN susceptibility, but the concept of genetic resilience, variants that protect against disease, remains understudied. Some individuals with high genetic risk do not develop AN, potentially due to resilience alleles that buffer risk loci (Hess et al., 2021; PMID: 31492941).
Research Questions:
1. Do genetic factors confer resistance to AN despite high genetic risk?
2. What is the heritability of AN resilience, and does it share causal variants with AN and other traits?
3. How does the AN resilience PRS correlate with psychological, metabol-ic, and anthropometric traits?
Aims:
1. Calculate an AN PRS in two cohorts (UK Biobank, Danish cohort).
2. Identify resilient vs. non-resilient individuals and conduct an AN resilience GWAS meta-analysis.
3. Derive an AN resilience PRS
4. Explore heritability for resilience to AN and perform colocalization anal-ysis to test for shared genetic causal variants with AN and other traits.
5. Explore genetic correlations and associations of the AN resilience PRS with diverse phenotypes.
Methods:
We will construct an AN PRS in the UK Biobank and Danish cohort. AN cases and controls with high AN PRS will be considered as “high-risk subsample”. This sub-sample will be determined by using in the 90th percentile and above of the AN PRS in the controls as lower and upper bound, respectively. AN cases within this range will be considered as non-resilient, while controls without AN in the same range will be considered as resilient. A GWAS of AN resilience will be conducted and meta-analyzed across cohorts.
The resilience GWAS will be used to calculate an AN resilience PRS in two addi-tional cohorts, assessing its correlation with diverse traits. Additional analyses in-clude fine-mapping, SNP-based heritability and colocalization analyses.