Familial influence on age of onset among siblings with Huntington disease

In order to provide data relevant to a search for modifying genes for age o f onset in Huntington disease, we examined the relationship between CAG num ber and age of onset in a total of 370 individuals from 165 siblingships, i n two cohorts of siblings with Huntington disease: an American group of 144 individuals from 64 siblingships, and a Canadian population of 255 individ uals from 113 siblingships, Using a logarithmic model to regress the age of onset on the number of CAG triplets, we found that CAG number alone accoun ted for 65%-71% of the variance in age of onset. The siblingship an individ ual belonged to accounted for 11%-19% of additional variance. This adds to the previous evidence that there are familial modifiers of the age of onset , independent of the CAG number. Such modifiers may consist of additional g enes, which could be the target of a linkage study. A linkage study is feas ible with the cooperation of a number of major centers and may be made more efficient by concentrating on sibling pairs that are highly discordant for age of onset. (C) 2001Wiley-Liss,Inc.