Genetic epidemiology of monogenic dyslipidemia and statin-associated adverse drug phenotypes in Indian population from whole-genomes of 1029 self-declared healthy individuals

Background: Monogenic dyslipidemia is a group of inherited genetic disorders characterized by abnormal levels of lipids and lipoproteins in blood, contributing to a significant risk for coronary artery diseases (CAD) and stroke. There is a paucity of prevalence estimates and genetic epidemiology of monogenic dyslipidemia in South Asian populations. The availability of population-scale genome sequencing datasets could potentially enable a better understanding of the genetic epidemiology of the disease.Methods: We analyzed whole-genome sequence data of 1029 healthy individuals from India to identify pathogenic variants in 24 genes associated with 26 primary monogenic dyslipidemias. The American College of Medical Genetics and Genomics (ACMG) guidelines was used to classify the variants. We also inferred statin-associated adverse drug phenotypes from SLCO1B1, ABCG2, and CYP2C9 genotypes/haplotypes.Results: Our analysis identified 12 pathogenic (P) and 9 likely pathogenic (LP) variants in 10 different genes. Autosomal dominant monogenic dyslipidemia prevalence ranged from 0.1% to 0.9%, while autosomal recessive disorder ranged from 0.000005% and 0.0005%. An infrequent 84/84 APOE genotype associated with hyper-cholesterolemia was found in 1% of samples. Our pharmacogenomic analysis revealed that 10% may require reduced dosage for most statins including atorvastatin, and 1.5% may require reduced dosage for rosuvastatin.Conclusion: Our study emphasizes the need for population-scale screening to enable early diagnosis and appropriate treatment of monogenic dyslipidemia in India. By identifying variants and estimating prevalence, our findings can inform healthcare providers in developing targeted prevention and management strategies to reduce cardiovascular disease risk.