Cell-type aware transcriptome-wide association study of mammographic density phenotypes.

Area of Science:

• Genetics
• Genomics
• Breast Cancer Research

Background:

• Mammographic density (MD) is highly heritable and a strong breast cancer risk factor.
• Genome-wide association studies (GWAS) have identified genetic variants for MD, but explain limited heritability.
• Transcriptome-wide association studies (TWAS) can identify genes linked to MD via genetically regulated gene expression (GReX), but bulk tissue analysis can obscure cell-type-specific effects.

Purpose of the Study:

• To conduct TWAS for MD phenotypes using standard and a novel cell-type-aware framework.
• To identify novel genes associated with MD and breast cancer risk.
• To improve the understanding of the genetic architecture of MD and its relationship with breast cancer.

Main Methods:

• A study population of 24,158 European ancestry women was analyzed.
• Mammographic density phenotypes (dense area, nondense area, percent density) were measured.
• Standard TWAS and a cell-type-aware TWAS (MiXcan2) were used to assess GReX associations with MD phenotypes.

Main Results:

• A total of 20 genes at 16 loci were significantly associated with MD phenotypes.
• Six novel genes at six loci, including THBS2-AS1, were identified.
• THBS2-AS1 was associated with decreased nondense area, increased percent density, and increased breast cancer risk.

Conclusions:

• Cell-type-aware TWAS identified novel genes for MD and breast cancer risk.
• The study highlights the importance of considering cell-type heterogeneity in genetic analyses of complex traits.
• This approach provides insights into the biological basis of dense versus nondense breast tissue and breast cancer susceptibility.