Multiple Sclerosis Heritability Estimation on Sardinian Ascertained Extended Families Using Bayesian Liability Threshold Model

INTRODUCTION: Narrow-sense heritability (h2 ) measures the proportion of phenotypic variability observed in a specific population that is attributable to the sum of additive genetic effects. Heritability studies represent an important tool to investigate the main sources of variability for complex diseases, whose etiology involves both genetics and environmental factors. AIM: The present work aimed to estimate multiple sclerosis (MS) narrow-sense heritability, on a liability scale, using 24 extended families ascertained from affected probands sampled in the Sardinian province of Nuoro, Italy. The sources of MS liability variability were also investigated among shared environmental effects, sex, and categorized year of birth (<1946, ≥1946). The latter can be considered a proxy for different early environmental exposures. METHODS: A Bayesian liability threshold model (Bayesian-LTMH) was developed to estimate heritability for binary phenotypes making use of ascertained family‐based samples, overcoming the limitations of the previously suggested EM algorithm. The Bayesian approach allows one to obtain the posterior distribution and credibility interval (CI) for heritability adjusted for potential confounders, such as shared environmental effects. The performance of Bayesian-LTMH was evaluated via simulation experiments and was then implemented to analyze the Sardinian families to obtain posterior distributions for the parameters of interest adjusting for ascertainment bias. RESULTS: Simulation studies highlighted the accuracy and precision of Bayesian-LTMH, other than the dramatic improvement in computational efficiency compared to the approach based on the EM algorithm. The analysis of the Sardinian sample highlighted categorized year of birth as the main explanatory factor, explaining ~70% of MS liability variability (median value = 0.69, 95% CI: 0.64, 0.73), while h2 resulted near to 0% (median value = 0.03, 95% CI: 0.00, 0.09). By performing a year of birth-stratified analysis, a high h2 was found only in individuals born on/after 1946 (median value = 0.82, 95% CI: 0.68, 0.93), meaning that the genetic variability had a high explanatory role only when focusing on this subpopulation. CONCLUSIONS: Overall, the results obtained highlighted early environmental exposures, in the Sardinian population, as a meaningful factor involved in MS to be further investigated. These environmental factors are likely linked to the westernization process that occurred in Sardinia after World War II. Among these the malaria eradication program has been previously pinpointed, under the light of the hygiene hypothesis, as a key factor to explain the dramatic rise in MS incidence in the last decades.