title: Adjusting for sex and anti-CCP levels in linkage analysis of rheumatoid arthritis.
abstract: We incorporate population effects of sex and antibodies directed against cyclic citrullinated peptides (anti-CCP) into the linkage analysis of rheumatoid arthritis (RA) with microsatellites data provided by the North American Rheumatoid Arthritis Consortium in Genetic Analysis Workshop 15.The method stems from a generalized linear mixed model that incorporates the marginal population effects of important covariates. The resulting test for linkage is based on a score test in a pseudo-likelihood of this model. The mathematical derivation is given elsewhere but the test has a simple and appealing form: it assigns weights to excess identity-by-descent sharing between pairs of related individuals depending on the individual-specific values of the covariates and phenotypes.Although RA is three times more prevalent in women than in men, the weights derived for male-male, female-male, and female-female affected sib pairs turn out to be very similar and the sex-adjusted analysis hardly differs from an unadjusted analysis. High anti-CCP levels are known to strongly predict RA. Our test assigns very small weights to pairs whose anti-CCP levels are high for the two siblings, sib pairs with two low anti-CCP levels are those most contributing to the evidence for linkage. Comparison of the unadjusted and the anti-CCP-adjusted analyses identifies persisting peaks mapping to regions that can be attributed to a 'dimension' of RA independent of anti-CCP.
authors.affiliation: Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, P,O, Box 9604, 2300 RC Leiden, The Netherlands. j.j.p.lebrec@lumc.nl
authors.forename: Jérémie J P
authors.initials: JJ
authors.lastname: Lebrec
authors.forename: Quinta
authors.initials: Q
authors.lastname: Helmer
authors.forename: Iryna
authors.initials: I
authors.lastname: Nishchenko
authors.forename: Hans C
authors.initials: HC
authors.lastname: van Houwelingen