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Many disorders cluster in families but are not associated with evident chromosomal aberrations or mendelian inheritance patterns. Examples include congenital malformations such as cleft lip, pyloric stenosis, and spina bifida; coronary artery disease; type 2 diabetes mellitus; and various forms of neoplasia. They are often characterized by varying frequencies in different racial or ethnic groups, disparity in sexual predilection, and greater frequency (but less than full concordance) in monozygotic than in dizygotic twins. This inheritance pattern is called "multifactorial" to signify that multiple genes interact with various environmental agents to produce the phenotype. The familial clustering is assumed to be due to sharing of both alleles and environment.

For most multifactorial conditions, there is little understanding of which particular genes are involved, how they and their products interact, and in what way different nongenetic factors contribute to the phenotype. For some disorders, biochemical and genetic studies have identified mendelian conditions within the coarse phenotype: Defects of the low-density lipoprotein receptor account for a small fraction of cases of ischemic heart disease (a larger fraction if only patients under age 50 years are considered); familial polyposis of the colon predisposes to adenocarcinoma; and some patients with emphysema have inherited deficiency of alpha-1-proteinase inhibitor (alpha-1-antitrypsin). Despite these notable examples, this reductionistic preoccupation with mendelian phenotypes is unlikely to explain the great majority of human disease; but even so, in the last analysis, much of human pathology will prove to be associated with genetic factors in cause, pathogenesis, or both.

Our ignorance about fundamental genetic mechanisms in development and physiology has not completely restricted practical approaches to the genetics of multifactorial disorders. For example, recurrence risks are based on empiric data derived from observation of many families. The risk of recurrence of multifactorial disorders is increased in several instances: (1) in close relatives (siblings, offspring, and parents) of an affected individual; (2) when two or more members of a family have the same condition; (3) when the first case in a family is in the less commonly affected sex (eg, pyloric stenosis is five times more common in boys; an affected woman has a threefold to fourfold greater risk of having a child with pyloric stenosis); and (4) in ethnic groups in which there is a high incidence of a particular condition (eg, spina bifida is 40 times more common in whites—and even more frequent among the Irish—than in Asians).

For many apparently multifactorial disorders, too few families have been examined to have established empiric risk data. A useful approximation of recurrence risk in close relatives is the square root of the incidence. For example, many common congenital malformations have an incidence of 1:2500 to 1:400 live births; the calculated recurrence risks are thus in the 2–5% range—values that correspond closely to experience.

Much effort has been directed at identifying the genetic contributors to multifactorial disease. Genome-wide association studies (GWAS) have included large cohorts of patients with a ...

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