A Statistical Testing Strategy Accounting for Random and Nonrandom (Skewed) X-Chromosome Inactivation Identifies Lung...

Area of Science:

• Genetics
• Oncology
• Epidemiology

Background:

• Lung cancer is a leading cause of cancer mortality worldwide.
• Sex differences in lung cancer risk, particularly among smokers, remain debated.
• Genome-wide association studies have largely excluded X-linked genetic loci.

Purpose of the Study:

• To investigate the role of X-linked genetic loci in lung cancer susceptibility.
• To develop and validate a statistical method accounting for X-inactivation processes.
• To identify novel lung cancer risk loci on the X chromosome.

Main Methods:

• Developed an additive-multiplicative hazard model for X-inactivation.
• Conducted a simulation study to compare statistical tests.
• Performed an X chromosome-wide association study on 9,261 individuals from the CARTaGENE cohort.
• Adjusted for the PLCOm2012 lung cancer risk score.

Main Results:

• The proposed statistical test demonstrated good power and type I error control.
• Identified two single nucleotide polymorphisms (SNPs) in the IL1RAPL1 gene (rs12558491 and rs12835699) associated with lower lung cancer risk.
• The minor alleles of these SNPs were linked to reduced lung cancer risk.
• Other statistical tests did not detect significant signals.

Conclusions:

• Investigating the X chromosome, considering smoking and X-inactivation, reveals new insights into lung cancer associations.
• Two novel X-linked loci in the IL1RAPL1 gene are associated with lung cancer risk.
• These findings underscore the importance of the proposed statistical approach for detecting X-linked genetic associations.