Family-based designs for genome-wide association studies

Linkage analysis has been hugely successful in identifying the genetic basis of many Mendelian disorders and the genetic contribution to some complex conditions. However, these approaches have been superseded in the past 15 years by association mapping and, more recently, by genome-wide association (GWA) studies.Present GWA approaches have difficulty detecting rare risk variants through linkage disequilibrium (LD) with common SNP markers; however, such variants can be found by linkage analysis. For example, BRCA1 and BRCA2, which are the most predominant of the known breast cancer susceptibility genes, were previously identified through linkage analysis but have not been identified by GWA studies.Typical linkage study designs include: parent–offspring trios, affected sibling pairs (sib-pairs), unselected sib-pairs or related individuals selected from the extremes of a quantitative trait distribution (for example, concordant or discordant sib-pairs), extended pedigrees with multiple affected individuals, consanguineous families and families obtained from isolated populations.A combination of linkage and association methodologies should provide the most accurate and powerful approach for identifying and characterizing the full range of disease-susceptibility variants. Family study designs offer: the ability to enrich for genetic loci containing rare variants; methods to control for heterogeneity and population stratification; direct estimates of the genetic contribution of different loci; the opportunity to examine the transmission of variants with phenotypes; and the ability to reveal the effects of parental origin of alleles.The problem of population heterogeneity is essentially non-existent in linkage analysis, so it has been tempting to use related individuals in genetic association studies as they are necessarily of the same ethnic origin (family-based as opposed to population-based controls). Another advantage of using family-based controls is that only family-based data will potentially exhibit genotyping errors in the form of Mendelian inconsistencies.These considerations motivate the search for a general framework to evaluate linkage and association simultaneously, taking combinations of data from pedigrees with different relationship structures (such as extended pedigrees, sibships or transmission disequilibrium test (TDT) families) and case–control samples. Such an approach is likely to be the most powerful approach for identifying new genetic factors related to trait loci, beyond those that can be readily detected by GWA in case–control designs.Prime examples of traits for which linkage and association mapping have been essential are Crohn's disease and fetal haemoglobin levels in adults.