Dataset Information

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

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.

SUBMITTER: Chen H

PROVIDER: S-EPMC9006574 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Publications

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

Chen Hongjie H Fan Shaoqi S Stone Jennifer J Thompson Deborah J DJ Douglas Julie J Li Shuai S Scott Christopher C Bolla Manjeet K MK Wang Qin Q Dennis Joe J Michailidou Kyriaki K Li Christopher C Peters Ulrike U Hopper John L JL Southey Melissa C MC Nguyen-Dumont Tu T Nguyen Tuong L TL Fasching Peter A PA Behrens Annika A Cadby Gemma G Murphy Rachel A RA Aronson Kristan K Howell Anthony A Astley Susan S Couch Fergus F Olson Janet J Milne Roger L RL Giles Graham G GG Haiman Christopher A CA Maskarinec Gertraud G Winham Stacey S John Esther M EM Kurian Allison A Eliassen Heather H Andrulis Irene I Evans D Gareth DG Newman William G WG Hall Per P Czene Kamila K Swerdlow Anthony A Jones Michael M Pollan Marina M Fernandez-Navarro Pablo P McConnell Daniel S DS Kristensen Vessela N VN Rothstein Joseph H JH Wang Pei P Habel Laurel A LA Sieh Weiva W Dunning Alison M AM Pharoah Paul D P PDP Easton Douglas F DF Gierach Gretchen L GL Tamimi Rulla M RM Vachon Celine M CM Lindström Sara S

Breast cancer research : BCR 20220412 1

<h4>Background</h4>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.<h4>Methods</h4>We conducted a genome-wide association study, as well as a transcriptome-wide association study (TWAS), of age- and BMI-adjusted DA, N ...[more]

PMID: 35414113

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Project description:Sole ulcers (SUs) and white line disease (WLD) are two common noninfectious claw lesions (NICL) that arise due to a compromised horn production and are frequent causes of lameness in dairy cattle, imposing welfare and profitability concerns. Low to moderate heritability estimates of SU and WLD susceptibility indicate that genetic selection could reduce their prevalence. To identify the susceptibility loci for SU, WLD, SU and/or WLD, and any type of noninfectious claw lesion, genome-wide association studies (GWAS) were performed using generalized linear mixed model (GLMM) regression, chunk-based association testing (CBAT), and a random forest (RF) approach. Cows from five commercial dairies in California were classified as controls having no lameness records and ≥6 years old (n = 102) or cases having SU (n = 152), WLD (n = 117), SU and/or WLD (SU + WLD, n = 198), or any type of noninfectious claw lesion (n = 217). The top single nucleotide polymorphisms (SNPs) were defined as those passing the Bonferroni-corrected suggestive and significance thresholds in the GLMM analysis or those that a validated RF model considered important. Effects of the top SNPs were quantified using Bayesian estimation. Linkage disequilibrium (LD) blocks defined by the top SNPs were explored for candidate genes and previously identified, functionally relevant quantitative trait loci. The GLMM and CBAT approaches revealed the same regions of association on BTA8 for SU and BTA13 common to WLD, SU + WLD, and NICL. These SNPs had effects significantly different from zero, and the LD blocks they defined explained a significant amount of phenotypic variance for each dataset (6.1-8.1%, p < 0.05), indicating the small but notable contribution of these regions to susceptibility. These regions contained candidate genes involved in wound healing, skin lesions, bone growth and mineralization, adipose tissue, and keratinization. The LD block defined by the most significant SNP on BTA8 for SU included a SNP previously associated with SU. The RF models were overfitted, indicating that the SNP effects were very small, thereby preventing meaningful interpretation of SNPs and any downstream analyses. These findings suggested that variants associated with various physiological systems may contribute to susceptibility for NICL, demonstrating the complexity of genetic predisposition.

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

Similar Datasets

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