Challenges in Identifying Genetic Risk Factors for Common Multifactorial Disorders (Commentary) (Report‪)‬

Advances in recombinant DNA technology have opened up many new diagnostic tools for monogenic disorders. DNA based techniques are also being used in the diagnosis of infectious diseases, and diagnosis and prognostication of cancers. Research in molecular pathogenesis of these disorders is likely to bring up new therapeutic strategies. The monogenic disorders account for a small part of mortality and morbidity in the general population, which is mainly contributed by complex multifactorial disorders like diabetes, hypertension, coronary artery disease, etc. Hence currently major research is directed towards identification of genetic risk factors for these common diseases. The aims are to develop diagnostic tests to identify the individuals at high risk and to develop novel preventive and therapeutic strategies. In spite of very good molecular, computational and statistical tools, the efforts in this direction have till date not been very fruitful. Most of the genetic risks for common disease must be conferred by low frequency alleles. (1) Most of these factors account for a small proportion of the total risk and their presence or absence will rarely increase or reduce recurrence risk of the relevant disorder more than two-fold. Thus, their diagnostic value is negligible. The most commonly used method to identify genetic risk factors for multifactorial disorders is association study which compares prevalence of a genotype in a group of patients with the disease in concern with that in the control population. When one reviews the literature over the last decade, it is seen that the genome wide association studies have often yielded contradictory results. Though billions of dollars have been spent to identify DNA variants in human genome that are more common in patients with a specific complex disease than in healthy individuals, the search for identification of major risk factors for complex disorders have remained elusive (1). Success is visible recently in exceptional situations like age related macular degeneration (2). Most association studies fail to identify the risk conferring allele not only due to insufficient sample size; but heterogeneity of the complex disorders (1). Polymorphisms in many genes interact with multiple known and unknown environmental factors ultimately resulting in the disease phenotype. It means that in each family and in each individual the contribution of various genetic variations to the disease phenotype may vary, and different combinations of different genetic variations may give rise to the similar phenotypes. Hence to get consistent and statistically significant results of association studies is difficult. This is obvious from the various studies of methylene tetrahydrofolate reductase (MTHFR) gene polymorphism in coronary artery disease and other thrombotic disorders.