Robust estimation of experimentwise P values applied to a genome scan of multiple asthma traits identifies a new region of significant linkage on chromosome 20q13.
Over 30 genomic regions show linkage to asthma traits. Six asthma genes have been cloned, but the putative loci in many linked regions have not been identified. To search for asthma susceptibility loci, we performed genomewide univariate linkage analyses of seven asthma traits, using 202 Australian families ascertained through a twin proband. House-dust mite sensitivity (Dpter) exceeded the empirical threshold for significant linkage at 102 cM on chromosome 20q13, near marker D20S173 (empirical pointwise P = .00001 and genomewide P = .005, both uncorrected for multiple-trait testing). Atopy, bronchial hyperresponsiveness (BHR), and forced expiratory volume in 1 s (FEV1) were also linked to this region. In addition, 16 regions were linked to at least one trait at the suggestive level, including 12q24, which has consistently shown linkage to asthma traits in other studies. Some regions were expected to be false-positives arising from multiple-trait testing. To address this, we developed a new approach to estimate genomewide significance that accounts for multiple-trait testing and for correlation between traits and that does not require a Bonferroni correction. With this approach, Dpter remained significantly linked to 20q13 (empirical genomewide P = .042), and airway obstruction remained linked to 12q24 at the suggestive level. Finally, we extended this method to show that the linkage of Dpter, atopy, BHR, FEV1, asthma, and airway obstruction to chromosome 20q13 is unlikely to be due to chance and may result from a quantitative trait locus in this region that affects several of these traits.
Ferreira
Manuel A R
MA
Queensland Institute of Medical Research, Brisbane, Australia. manuelF@qimr.edu.au
O'Gorman
Louise
L
Le Souëf
Peter
P
Burton
Paul R
PR
Toelle
Brett G
BG
Robertson
Colin F
CF
Visscher
Peter M
PM
Martin
Nicholas G
NG
Duffy
David L
DL
D000328:Adult; D000368:Aged; D000818:Animals; D001249:Asthma / Q000235:genetics* / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000235:genetics; D002874:Chromosome Mapping; D002881:Chromosomes, Human, Pair 12; D002890:Chromosomes, Human, Pair 20; D040002:Dermatophagoides pteronyssinus / Q000276:immunology; D005260:Female; D005541:Forced Expiratory Volume / Q000235:genetics; D008040:Genetic Linkage; D005819:Genetic Markers; D015894:Genome, Human; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011336:Probability; D040641:Quantitative Trait Loci / Q000235:genetics*; D012882:Skin Tests
D005819:Genetic Markers