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. 2022 Apr 12;24(1):27.
doi: 10.1186/s13058-022-01524-0.

Genome-wide and transcriptome-wide association studies of mammographic density phenotypes reveal novel loci

Hongjie Chen  1 , Shaoqi Fan  2 , Jennifer Stone  3 , Deborah J Thompson  4 , Julie Douglas  5   6 , Shuai Li  4   7   8 , Christopher Scott  9 , Manjeet K Bolla  4 , Qin Wang  4 , Joe Dennis  4 , Kyriaki Michailidou  10   11 , Christopher Li  1   12 , Ulrike Peters  1   12 , John L Hopper  7 , Melissa C Southey  8 , Tu Nguyen-Dumont  8 , Tuong L Nguyen  7 , Peter A Fasching  13 , Annika Behrens  13 , Gemma Cadby  3 , Rachel A Murphy  14 , Kristan Aronson  15 , Anthony Howell  16 , Susan Astley  17 , Fergus Couch  9 , Janet Olson  9 , Roger L Milne  7   8   18 , Graham G Giles  7   17   18 , Christopher A Haiman  19 , Gertraud Maskarinec  20 , Stacey Winham  9 , Esther M John  21   22   23 , Allison Kurian  21   22   23 , Heather Eliassen  24   25 , Irene Andrulis  26   27 , D Gareth Evans  28   29   30 , William G Newman  28 , Per Hall  31 , Kamila Czene  31 , Anthony Swerdlow  32 , Michael Jones  32 , Marina Pollan  33 , Pablo Fernandez-Navarro  33 , Daniel S McConnell  34 , Vessela N Kristensen  35 ; NBCS Investigators; Joseph H Rothstein  36   37 , Pei Wang  37 , Laurel A Habel  38 , Weiva Sieh  36   37 , Alison M Dunning  4 , Paul D P Pharoah  4 , Douglas F Easton  4 , Gretchen L Gierach  2 , Rulla M Tamimi  39 , Celine M Vachon  9 , Sara Lindström  40   41
Affiliations

Genome-wide and transcriptome-wide association studies of mammographic density phenotypes reveal novel loci

Hongjie Chen et al. Breast Cancer Res. .

Abstract

Background: Mammographic density (MD) phenotypes, including percent density (PMD), area of dense tissue (DA), and area of non-dense tissue (NDA), are associated with breast cancer risk. Twin studies suggest that MD phenotypes are highly heritable. However, only a small proportion of their variance is explained by identified genetic variants.

Methods: We conducted a genome-wide association study, as well as a transcriptome-wide association study (TWAS), of age- and BMI-adjusted DA, NDA, and PMD in up to 27,900 European-ancestry women from the MODE/BCAC consortia.

Results: We identified 28 genome-wide significant loci for MD phenotypes, including nine novel signals (5q11.2, 5q14.1, 5q31.1, 5q33.3, 5q35.1, 7p11.2, 8q24.13, 12p11.2, 16q12.2). Further, 45% of all known breast cancer SNPs were associated with at least one MD phenotype at p < 0.05. TWAS further identified two novel genes (SHOX2 and CRISPLD2) whose genetically predicted expression was significantly associated with MD phenotypes.

Conclusions: Our findings provided novel insight into the genetic background of MD phenotypes, and further demonstrated their shared genetic basis with breast cancer.

Keywords: Breast cancer; Genome-wide association study (GWAS); Mammographic density; Transcriptome-wide association study (TWAS).

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Manhattan plots of the GWAS meta-analysis results of mammographic a dense area (DA, N = 24,579), b non-dense area (NDA, N = 24,689), and c percent mammographic density (PMD, N = 27,900). p value thresholds for genome-wide significance (p = 5 × 10−8, red dash line) and suggestive significance (p = 10−5, blue dash line) are shown as horizontal lines. The gene closest to each lead variant is annotated. Novel loci are marked red. a Manhattan plot of the GWAS meta-analysis results of DA. b Manhattan plot of the GWAS meta-analysis results of NDA. c Manhattan plot of the GWAS meta-analysis results of PMD
Fig. 1
Fig. 1
Manhattan plots of the GWAS meta-analysis results of mammographic a dense area (DA, N = 24,579), b non-dense area (NDA, N = 24,689), and c percent mammographic density (PMD, N = 27,900). p value thresholds for genome-wide significance (p = 5 × 10−8, red dash line) and suggestive significance (p = 10−5, blue dash line) are shown as horizontal lines. The gene closest to each lead variant is annotated. Novel loci are marked red. a Manhattan plot of the GWAS meta-analysis results of DA. b Manhattan plot of the GWAS meta-analysis results of NDA. c Manhattan plot of the GWAS meta-analysis results of PMD
Fig. 1
Fig. 1
Manhattan plots of the GWAS meta-analysis results of mammographic a dense area (DA, N = 24,579), b non-dense area (NDA, N = 24,689), and c percent mammographic density (PMD, N = 27,900). p value thresholds for genome-wide significance (p = 5 × 10−8, red dash line) and suggestive significance (p = 10−5, blue dash line) are shown as horizontal lines. The gene closest to each lead variant is annotated. Novel loci are marked red. a Manhattan plot of the GWAS meta-analysis results of DA. b Manhattan plot of the GWAS meta-analysis results of NDA. c Manhattan plot of the GWAS meta-analysis results of PMD
Fig. 2
Fig. 2
Manhattan-like plots showing the association between genome-wide significant breast cancer SNPs and the three mammographic density phenotypes (DA, NDA, PMD). p value thresholds for genome-wide significance (p = 5 × 10−8, red line), suggestive significance (p = 10−5, blue line) and nominal significance (p = 0.05, green line) are shown as horizontal dash lines. For signals with genome-wide significance for both MD phenotype and breast cancer, the nearest gene is annotated. a GWAS results of DA for significant SNPs of breast cancer. b GWAS results of NDA for significant SNPs of breast cancer. c GWAS results of PMD for significant SNPs of breast cancer
Fig. 2
Fig. 2
Manhattan-like plots showing the association between genome-wide significant breast cancer SNPs and the three mammographic density phenotypes (DA, NDA, PMD). p value thresholds for genome-wide significance (p = 5 × 10−8, red line), suggestive significance (p = 10−5, blue line) and nominal significance (p = 0.05, green line) are shown as horizontal dash lines. For signals with genome-wide significance for both MD phenotype and breast cancer, the nearest gene is annotated. a GWAS results of DA for significant SNPs of breast cancer. b GWAS results of NDA for significant SNPs of breast cancer. c GWAS results of PMD for significant SNPs of breast cancer
Fig. 2
Fig. 2
Manhattan-like plots showing the association between genome-wide significant breast cancer SNPs and the three mammographic density phenotypes (DA, NDA, PMD). p value thresholds for genome-wide significance (p = 5 × 10−8, red line), suggestive significance (p = 10−5, blue line) and nominal significance (p = 0.05, green line) are shown as horizontal dash lines. For signals with genome-wide significance for both MD phenotype and breast cancer, the nearest gene is annotated. a GWAS results of DA for significant SNPs of breast cancer. b GWAS results of NDA for significant SNPs of breast cancer. c GWAS results of PMD for significant SNPs of breast cancer
Fig. 3
Fig. 3
Genetic correlations between three MD phenotypes (DA, NDA, PMD) and breast cancer (overall, ER-positive, and ER-negative), estimated by LD score regression
See this image and copyright information in PMC

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