A General Test of Association for Quantitative Traits in Nuclear Families

Abstract

High-resolution mapping is an important step in the identification of complex disease genes. In outbred populations, linkage disequilibrium is expected to operate over short distances and could provide a powerful fine-mapping tool. Here we build on recently developed methods for linkage-disequilibrium mapping of quantitative traits to construct a general approach that can accommodate nuclear families of any size, with or without parental information. Variance components are used to construct a test that utilizes information from all available offspring but that is not biased in the presence of linkage or familiality. A permutation test is described for situations in which maximum-likelihood estimates of the variance components are biased. Simulation studies are used to investigate power and error rates of this approach and to highlight situations in which violations of multivariate normality assumptions warrant the permutation test. The relationship between power and the level of linkage disequilibrium for this test suggests that the method is well suited to the analysis of dense maps. The relationship between power and family structure is investigated, and these results are applicable to study design in complex disease, especially for late-onset conditions for which parents are usually not available. When parental genotypes are available, power does not depend greatly on the number of offspring in each family. Power decreases when parental genotypes are not available, but the loss in power is negligible when four or more offspring per family are genotyped. Finally, it is shown that, when siblings are available, the total number of genotypes required in order to achieve comparable power is smaller if parents are not genotyped.

Association between the 2-bp deletion polymorphism in the duplicated version of the alpha7 nicotinic receptor gene and P50 sensory gating

“…Supporting this, we found that tests of population stratification for these genetic variants were significant, indicating that only the within-family association test is valid and suggesting that significant between-family association may have been masked by population stratification. 59 Similar results were found for other associations. 63,64 Although our cohort were all white Caucasians, some genetic heterogeneity within this ethnic group would not be surprising.…”

“…As Transmit will not accept twinships, dizygous (DZ) twins were entered as siblings while one twin per MZ pair were entered as above. To perform tests for association on continuous phenotype scores we used QTDT (http://www.sph.umich.edu/csg/abecasis/QTDT/), 59,60 which incorporates a modified form of TDT. QTDT will construct possible parental genotypes where absent and accepts all types of sibships.…”

The SNAP-25 gene is associated with cognitive ability: evidence from a family-based study in two independent Dutch cohorts

“…Genetic association tests were conducted using the program QTDT, which implements the orthogonal association model proposed by Abecasis et al 39 (see also Fulker et al; 40 extended by Posthuma et al 41 ). This model allows the decomposition of the genotypic association effect into orthogonal between-(b b ) and within-(b w ) family components, can incorporate fixed effects of covariates and can also model the residual sib-correlation as a function of polygenic or environmental factors.…”

Renal function in relation to three candidate genes in a Chinese population

“…The amplification conditions were 50 C for 2 min and 95 C for 10 min, followed by 40 cycles at 95 C for 15 s and 61 C for 1 min. [24]. With similar adjustments as in the other analyses, we investigated the association between the renal phenotypes and allelic transmission using the orthogonal model in a variance decomposition framework [25].…”