Linkage analysis using co-phenotypes in the BRIGHT study reveals novel potential susceptibility loci for hypertension.
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.
Wallace
Chris
C
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
Xue
Ming-Zhan
MZ
Newhouse
Stephen J
SJ
Marcano
Ana Carolina B
AC
Onipinla
Abiodun K
AK
Burke
Beverley
B
Gungadoo
Johannie
J
Dobson
Richard J
RJ
Brown
Morris
M
Connell
John M
JM
Dominiczak
Anna
A
Lathrop
G Mark
GM
Webster
John
J
Farrall
Martin
M
Mein
Charles
C
Samani
Nilesh J
NJ
Caulfield
Mark J
MJ
Clayton
David G
DG
Munroe
Patricia B
PB
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
D005819:Genetic Markers