Genetic studies of late diabetic complications: the overlooked importance of diabetes duration before complication onset.

Genes play a role in many processes underlying late diabetic complications, but efforts to identify genetic variants have produced disappointing and contradictory results. Here, we evaluate whether the study designs and analytic methods commonly being used are optimal for finding susceptibility genes for diabetic complications. We do so by generating plausible genetic models and assessing the performance of case-control and family-based trio study designs. What emerges as a key determinant of success is duration of diabetes. This perspective focuses on duration of diabetes before complication onset and its influence on the ability to detect major and minor gene effects. It does not delve into the distinct effect of duration after complication onset, which can enrich case subjects with genotypes conferring survival advantage. We use clinically diagnosed nephropathy in type 1 diabetes to show how ignoring duration can result in considerable power loss in both case-control and family-based trio designs. We further show how, under certain circumstances, disregard for duration information can paradoxically lead to implicating nonrisk alleles as causative. Our results indicate that problems can be minimized by selecting case subjects with short diabetes duration and, to a lesser extent, control subjects with long duration or, perhaps, by adjusting for duration during analysis.