Increasing the power of association studies with affected families, unrelated cases and controls.

When studying the genetics of inherited diseases, researchers often collect data on affected families, unrelated cases, and healthy controls. However, the joint analysis of such heterogeneous data is difficult, and the simpler analysis of homogeneous subsets is often suboptimal. For example, while case-control tests of association are sensitive to allele frequency differences, the preferential transmission of risk alleles from heterozygous parents to their affected offspring is typically ignored. Similarly, the transmission disequilibrium test (TDT) fails to incorporate the difference in allele frequencies when testing for association. To boost the power of modern genetic studies, we propose POPFAM - a fast and efficient test of association that can accommodate large affected families, unrelated cases, and controls. We use simulations to assess the type I error and power of POPFAM across different genetic models, and minor allele frequencies. For comparison, we examine the power of competing methods: the trend test, a Wald test (equivalent to the TDT), and SCOUT. Our results show that POPFAM maintains the correct type I error, and that it is more powerful than the trend test or the TDT. It performs as well as, or better than the likelihood ratio test SCOUT, which was developed specifically for case-parent/case-control data. Furthermore, when applied to the human leukocyte antigen genotypes of 401 type 1 diabetic families, POPFAM confirmed the previously reported association between DRB1(*)03:01 and microvascular complications (p = 0.04). In general, we expect our proposed test to facilitate the identification of clinically important genomic regions, and to better inform the design of follow-up sequencing efforts.