title: Linkage analysis using co-phenotypes in the BRIGHT study reveals novel potential susceptibility loci for hypertension.
abstract: Identification of the genetic influences on human essential hypertension and other complex diseases has proved difficult, partly because of genetic heterogeneity. In many complex-trait resources, additional phenotypic data have been collected, allowing comorbid intermediary phenotypes to be used to characterize more genetically homogeneous subsets. The traditional approach to analyzing covariate-defined subsets has typically depended on researchers' previous expectations for definition of a comorbid subset and leads to smaller data sets, with a concomitant attrition in power. An alternative is to test for dependence between genetic sharing and covariates across the entire data set. This approach offers the advantage of exploiting the full data set and could be widely applied to complex-trait genome scans. However, existing maximum-likelihood methods can be prohibitively computationally expensive, especially since permutation is often required to determine significance. We developed a less computationally intensive score test and applied it to biometric and biochemical covariate data, from 2,044 sibling pairs with severe hypertension, collected by the British Genetics of Hypertension (BRIGHT) study. We found genomewide-significant evidence for linkage with hypertension and several related covariates. The strongest signals were with leaner-body-mass measures on chromosome 20q (maximum LOD = 4.24) and with parameters of renal function on chromosome 5p (maximum LOD = 3.71). After correction for the multiple traits and genetic locations studied, our global genomewide P value was .046. This is the first identity-by-descent regression analysis of hypertension to our knowledge, and it demonstrates the value of this approach for the incorporation of additional phenotypic information in genetic studies of complex traits.
authors.affiliation: Clinical Pharmacology and The Genome Centre, The William Harvey Research Institute, Barts and The London, Queen Mary's School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, UK. c.wallace@qmul.ac.uk
authors.forename: Chris
authors.initials: C
authors.lastname: Wallace
authors.forename: Ming-Zhan
authors.initials: MZ
authors.lastname: Xue
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Newhouse
authors.forename: Ana Carolina B
authors.initials: AC
authors.lastname: Marcano
authors.forename: Abiodun K
authors.initials: AK
authors.lastname: Onipinla
authors.forename: Beverley
authors.initials: B
authors.lastname: Burke
authors.forename: Johannie
authors.initials: J
authors.lastname: Gungadoo
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Dobson
authors.forename: Morris
authors.initials: M
authors.lastname: Brown
authors.forename: John M
authors.initials: JM
authors.lastname: Connell
authors.forename: Anna
authors.initials: A
authors.lastname: Dominiczak
authors.forename: G Mark
authors.initials: GM
authors.lastname: Lathrop
authors.forename: John
authors.initials: J
authors.lastname: Webster
authors.forename: Martin
authors.initials: M
authors.lastname: Farrall
authors.forename: Charles
authors.initials: C
authors.lastname: Mein
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Caulfield
authors.forename: David G
authors.initials: DG
authors.lastname: Clayton
authors.forename: Patricia B
authors.initials: PB
authors.lastname: Munroe
mesh_terms: D002874:Chromosome Mapping; D005260:Female; D008040:Genetic Linkage; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D006113:United Kingdom
chemical_list: D005819:Genetic Markers