Genome-wide association study in discordant sibships identifies multiple inherited susceptibility alleles linked to lung cancer.
We analyzed a series of young (median age = 52 years) non-smoker lung cancer patients and their unaffected siblings as controls, using a genome-wide 620 901 single-nucleotide polymorphism (SNP) array analysis and a case-control DNA pooling approach. We identified 82 putatively associated SNPs that were retested by individual genotyping followed by use of the sib transmission disequilibrium test, pointing to 36 SNPs associated with lung cancer risk in the discordant sibs series. Analysis of these 36 SNPs in a polygenic model characterized by additive and interchangeable effects of rare alleles revealed a highly statistically significant dosage-dependent association between risk allele carrier status and proportion of cancer cases. Replication of the same 36 SNPs in a population-based series confirmed the association with lung cancer for three SNPs, suggesting that phenocopies and genetic heterogeneity can play a major role in the complex genetics of lung cancer risk in the general population.
Galvan
Antonella
A
Fondazione IRCCS, Istituto Nazionale Tumori, 20133 Milan, Italy.
Falvella
Felicia S
FS
Frullanti
Elisa
E
Spinola
Monica
M
Incarbone
Matteo
M
Nosotti
Mario
M
Santambrogio
Luigi
L
Conti
Barbara
B
Pastorino
Ugo
U
Gonzalez-Neira
Anna
A
Dragani
Tommaso A
TA
D000230:Adenocarcinoma / Q000453:epidemiology / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D016022:Case-Control Studies; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007558:Italy / Q000453:epidemiology; D015810:Linkage Disequilibrium; D008175:Lung Neoplasms / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D035781:Siblings
D004273:DNA, Neoplasm