Comprehensive testing of positionally cloned asthma genes in two populations.
BACKGROUND
Replication of gene-disease associations has become a requirement in complex trait genetics.


OBJECTIVE
In studies of childhood asthma from two different ethnic groups, we attempted to replicate associations with five potential asthma susceptibility genes previously identified by positional cloning.


METHODS
We analyzed two family-based samples ascertained through an asthmatic proband: 497 European-American children from the Childhood Asthma Management Program and 439 Hispanic children from the Central Valley of Costa Rica. We genotyped 98 linkage disequilibrium-tagging single-nucleotide polymorphisms (SNPs) in five genes: ADAM33, DPP10, GPR154 (HUGO name: NPSR1), HLA-G, and the PHF11 locus (includes genes SETDB2 and RCBTB1). SNPs were tested for association with asthma and two intermediate phenotypes: airway hyperresponsiveness and total serum immunoglobulin E levels.


RESULTS
Despite differing ancestries, linkage disequilibrium patterns were similar in both cohorts. Of the five evaluated genes, SNP-level replication was found only for GPR154 (NPSR1). In this gene, three SNPs were associated with asthma in both cohorts, although the opposite alleles were associated in either study. Weak evidence for locus-level replication with asthma was found in the PHF11 locus, although there was no overlap in the associated SNP across the two cohorts. No consistent associations were observed for the three other genes.


CONCLUSIONS
These results provide some further support for the role of genetic variation in GPR154 (NPSR1) and PHF11 in asthma susceptibility and also highlight the challenges of replicating genetic associations in complex traits such as asthma, even for genes identified by linkage analysis.
Hersh
Craig P
CP
Channing Laboratory and Center for Genomic Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. craig.hersh@channing.harvard.edu
Raby
Benjamin A
BA
Soto-Quirós
Manuel E
ME
Murphy
Amy J
AJ
Avila
Lydiana
L
Lasky-Su
Jessica
J
Sylvia
Jody S
JS
Klanderman
Barbara J
BJ
Lange
Christoph
C
Weiss
Scott T
ST
Celedón
Juan C
JC
D051722:ADAM Proteins / Q000235:genetics; D000293:Adolescent; D001249:Asthma / Q000208:ethnology* / Q000235:genetics*; D002648:Child; D003001:Cloning, Molecular; D003364:Costa Rica; D004268:DNA-Binding Proteins / Q000235:genetics*; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000235:genetics; D005260:Female; D023061:Gene Order; D006680:HLA Antigens / Q000235:genetics; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D006801:Humans; D007197:Indians, Central American / Q000235:genetics*; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D009656:North America; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D044465:White People / Q000235:genetics*
D004268:DNA-Binding Proteins; D006680:HLA Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I; C484532:NPSR1 protein, human; C493258:PHF11 protein, human; D043562:Receptors, G-Protein-Coupled; D014157:Transcription Factors; C476879:DPP10 protein, human; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D051722:ADAM Proteins; C450441:ADAM33 protein, human
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