"No substantial study of normal sib-pairs has been undertaken, making this family of surveys one of the largest undertaken in the absence of controls" . The two main motivations for this study are reports of transmission ratio distortion at a number of loci in humans and the often nonsignificant results of genetic linkage studies of complex diseases.
Transmission ratio distortion (TRD) has been defined as "a statistically significant departure from the Mendelian inheritance ratio expected regardless of the cause" . There are a number of reports indicating that TRD may be present at specific regions in the human genome (reviewed in ), but many are based on families with multiple individuals affected with a particular disease, making it difficult to determine whether such phenomena are somehow related to the disease, or are a general occurrence. In some cases, families not recruited for disease have been used, but some of these, such as the Centre d'Etude du Polymorphisme Humain (CEPH) reference families, were specifically ascertained for their large sibship sizes and the availability of grandparents. Use of such pedigrees may reduce the proportion of families demonstrating TRD compared with the general population (see Discussion). Furthermore, attempts to identify TRD loci have not been performed in a systematic genome-wide fashion: regions have been selected either for the presence of putative disease susceptibility loci (e.g., ); or loci that contain genes that have been documented to demonstrate genomic imprinting [4, 5].
At certain TRD loci, the effect may be sex-specific [3–5], and this may have important implications for the mapping of loci for common complex disease. Sex differences in the age-specific incidence are a general feature of common complex diseases. Obviously, certain diseases either solely (e.g., ovarian cancer, prostate cancer), or predominantly (e.g., breast cancer, systemic lupus erythematosus, autism) affect individuals of one gender. Due to theoretical considerations, most genetic mapping studies of common complex diseases have employed affected sib pairs only . In fact, unaffected siblings are rarely recruited or genotyped since it has been argued that unless the prevalence of the trait is high, they do not provide sufficient linkage information to justify study . Thus any locus that produces TRD in a sex-specific fashion would be expected to also demonstrate evidence for linkage to a disease in which the majority of affected individuals were of that gender-and this would likely be spurious linkage . There have been reports of sex-specific autosomal loci for some complex diseases, but it has generally not been possible to determine whether these are spurious linkages with disease resulting from sex-specific TRD because of the paucity of genotyped unaffected sibs. Finally, genetic linkage studies of complex diseases have generally produced nonsignificant results using genome-wide criteria. This makes it difficult to distinguish true linkage signals from noise. Noise from biological phenomenon such as TRD could therefore potentially mislead disease gene mapping efforts.
The Framingham families represent a valuable resource for the study of TRD because they are relatively ethnically homogeneous (predominantly White), and were not recruited for the presence of disease or trait value. The only reasons that families were included in the genetic studies was based on their age being 28-62 years for the original cohort and 12-58 years for the offspring cohort at recruitment, being alive when DNA was obtained (in the late 1980s and early 1990s), and their relatively large size (although the exact criteria used to determine size were not specified). Results from these families will help to determine whether concerns about TRD are of general concern for the mapping of susceptibility loci for complex diseases.