Linkage analysis of ordinal traits for pedigree data

Abstract

Linkage analysis is used routinely to map genes for human diseases and conditions. However, the existing linkage-analysis methods require that the diseases or conditions either be dichotomized or measured by a quantitative trait, such as blood pressure for hypertension. In the latter case, normality is generally assumed for the trait. However, many diseases and conditions, such as cancer and mental and behavioral conditions, are rated on ordinal scales. The objective of this study was to establish a framework to conduct linkage analysis for ordinal traits. We propose a latent-variable, proportional-odds logistic model that relates inheritance patterns to the distribution of the ordinal trait. We use the likelihood-ratio test for testing evidence of linkage. By means of simulation studies, we find that the power of our proposed model is substantially higher than that of the binary-trait-based linkage analysis and that our test statistic is robust with regard to certain parameter misspecifications. By using our proposed method, we performed a genome scan of the hoarding phenotype in a data set with 53 nuclear families, which were collected by the Tourette Syndrome Association International Consortium for Genetics (TSAICG). Standard linkage scans using hoarding as a dichotomous trait were also performed by using GENEHUNTER and ALLEGRO. Both GENEHUNTER and ALLEGRO failed to reveal any marker significantly linked to the binary hoarding phenotypes. However, our method identified three markers at 4q34-35 (P ‫؍‬ 0.0009), 5q35.2-35.3 (P ‫؍‬ 0.0001), and 17q25 (P ‫؍‬ 0.0005) that manifest significant allele sharing.

Family‐based association tests for ordinal traits adjusting for covariates

“…Similarly, it is inappropriate to treat ordinal traits as if they were continuous and assume normality. Feng et al [2004] developed a linkage analysis framework of ordinal traits for pedigree data using a proportional odds latent variable model. Zhang et al [2006] proposed a score test for association studies of ordinal traits.…”

“…This calls for the development of methods to conduct genetic analyses of ordinal traits. Some of the reports, thus far [e.g., Zhang et al, 2003Zhang et al, , 2006Feng et al, 2004] …”

Detection of Genes for Ordinal Traits in Nuclear Families and a Unified Approach for Association Studies

“…An unnecessary collapse of trait levels could reduce the power in genetic analyses (Zhang et al 2003;Feng et al 1 2004). Although Zhang et al (2003) and Feng et al (2004) developed a basic framework to conduct segregation and linkage analyses for pedigree data, methods have not been developed for the association analysis of ordinal traits.…”

“…As illustrated by Zhang et al (2003) and Feng et al (2004), many human conditions (e.g., cancer and most behavioral and psychiatric disorders) are measured on discrete, ordinal scales. An unnecessary collapse of trait levels could reduce the power in genetic analyses (Zhang et al 2003;Feng et al 1 2004).…”

A genomic imprinting test for ordinal traits in pedigree data

“…Furthermore, most methods to test imprinting are limited to sibs, relative pairs, or case-parent triads [Weinberg, 1999;Hanson et al, 2001;Karason et al, 2003;Knapp and Strauch, 2004;Vincent et al, 2006]. Using large pedigree information directly can lead to more efficient and more powerful methods than dividing pedigrees into sibs [Wijsman and Amos, 1997;Shete et al, 2003], but only a few can be applied for extended pedigrees [Strauch et al, 2000;Shete et al, 2003].In a previous study, we developed a latent variable model and used a likelihood ratio test to map genes for ordinal traits from pedigree data that showed increased power compared with methods using dichotomized traits [Feng et al, 2004]. However, computation of the likelihood ratio in relatively large pedigrees is overwhelming and often infeasible.…”