An extension of the classical twin study is the children-of-twins (COT) design which compares outcomes in offspring of twins. Using data on children of affected and unaffected MZ and DZ pairs, four groups can be defined: (1) high genetic risk and high environmental risk (parent, MZ or DZ, is affected), (2) high genetic risk but reduced environmental risk (parent is unaffected but parent’s MZ twin is affected), (3) intermediate genetic risk but reduced environmental risk (parent is unaffected but parent’s DZ twin is affected), and (4) children at low genetic and low environmental risk (parent and co-twin are both unaffected). The COT design allows for detection of genetic transmission that could in principle account for associations between an apparent environmental risk-factor and offspring outcomes27. It can also be used to detect the environmental consequences of parental substance use disorders that may or may not depend upon offspring genetic vulnerability or be masked by genetic non-additivity and therefore remain undetected in the traditional twin study design.
