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Identification of novel breast cancer susceptibility loci in meta-analyses conducted among Asian and European descendants.

ABSTRACT: Known risk variants explain only a small proportion of breast cancer heritability, particularly in Asian women. To search for additional genetic susceptibility loci for breast cancer, here we perform a meta-analysis of data from genome-wide association studies (GWAS) conducted in Asians (24,206 cases and 24,775 controls) and European descendants (122,977 cases and 105,974 controls). We identified 31 potential novel loci with the lead variant showing an association with breast cancer risk at P?-8. The associations for 10 of these loci were replicated in an independent sample of 16,787 cases and 16,680 controls of Asian women (P?

SUBMITTER: Shu X

PROVIDER: S-EPMC7057957 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Identification of novel breast cancer susceptibility loci in meta-analyses conducted among Asian and European descendants.

Shu Xiang X Long Jirong J Cai Qiuyin Q Kweon Sun-Seog SS Choi Ji-Yeob JY Kubo Michiaki M Park Sue K SK Bolla Manjeet K MK Dennis Joe J Wang Qin Q Yang Yaohua Y Shi Jiajun J Guo Xingyi X Li Bingshan B Tao Ran R Aronson Kristan J KJ Chan Kelvin Y K KYK Chan Tsun L TL Gao Yu-Tang YT Hartman Mikael M Kee Ho Weang W Ito Hidemi H Iwasaki Motoki M Iwata Hiroji H John Esther M EM Kasuga Yoshio Y Soon Khoo Ui U Kim Mi-Kyung MK Kong Sun-Young SY Kurian Allison W AW Kwong Ava A Lee Eun-Sook ES Li Jingmei J Lophatananon Artitaya A Low Siew-Kee SK Mariapun Shivaani S Matsuda Koichi K Matsuo Keitaro K Muir Kenneth K Noh Dong-Young DY Park Boyoung B Park Min-Ho MH Shen Chen-Yang CY Shin Min-Ho MH Spinelli John J JJ Takahashi Atsushi A Tseng Chiuchen C Tsugane Shoichiro S Wu Anna H AH Xiang Yong-Bing YB Yamaji Taiki T Zheng Ying Y Milne Roger L RL Dunning Alison M AM Pharoah Paul D P PDP García-Closas Montserrat M Teo Soo-Hwang SH Shu Xiao-Ou XO Kang Daehee D Easton Douglas F DF Simard Jacques J Zheng Wei W

Nature communications 20200305 1

Known risk variants explain only a small proportion of breast cancer heritability, particularly in Asian women. To search for additional genetic susceptibility loci for breast cancer, here we perform a meta-analysis of data from genome-wide association studies (GWAS) conducted in Asians (24,206 cases and 24,775 controls) and European descendants (122,977 cases and 105,974 controls). We identified 31 potential novel loci with the lead variant showing an association with breast cancer risk at P < ...[more]

PMID: 32139696

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Project description:BackgroundThe functions of most glioma risk alleles are unknown. Very few studies had evaluated expression quantitative trait loci (eQTL), and insights of susceptibility genes were limited due to scarcity of available brain tissues. Moreover, no prior study had examined the effect of glioma risk alleles on alternative RNA splicing.ObjectiveThis study explored splicing quantitative trait loci (sQTL) as molecular QTL and improved the power of QTL mapping through meta-analyses of both cis eQTL and sQTL.MethodsWe first evaluated eQTLs and sQTLs of the CommonMind Consortium (CMC) and Genotype-Tissue Expression Project (GTEx) using genotyping, or whole-genome sequencing and RNA-seq data. Alternative splicing events were characterized using an annotation-free method that detected intron excision events. Then, we conducted meta-analyses by pooling the eQTL and sQTL results of CMC and GTEx using the inverse variance-weighted model. Afterward, we integrated QTL meta-analysis results (Q < 0.05) with the Glioma International Case Control Study (GICC) GWAS meta-analysis (case:12,496, control:18,190), using a summary statistics-based mendelian randomization (SMR) method.ResultsBetween CMC and GTEx, we combined the QTL data of 354 unique individuals of European ancestry. SMR analyses revealed 15 eQTLs in 11 loci and 32 sQTLs in 9 loci relevant to glioma risk. Two loci only harbored sQTLs (1q44 and 16p13.3). In seven loci, both eQTL and sQTL coexisted (2q33.3, 7p11.2, 11q23.3 15q24.2, 16p12.1, 20q13.33, and 22q13.1), but the target genes were different for five of these seven loci. Three eQTL loci (9p21.3, 20q13.33, and 22q13.1) and 4 sQTL loci (11q23.3, 16p13.3, 16q12.1, and 20q13.33) harbored multiple target genes. Eight target genes of sQTLs (C2orf80, SEC61G, TMEM25, PHLDB1, RP11-161M6.2, HEATR3, RTEL1-TNFRSF6B, and LIME1) had multiple alternatively spliced transcripts.ConclusionOur study revealed that the regulation of transcriptome by glioma risk alleles is complex, with the potential for eQTL and sQTL jointly affecting gliomagenesis in risk loci. QTLs of many loci involved multiple target genes, some of which were specific to alternative splicing. Therefore, quantitative trait loci that evaluate only total gene expression will miss many important target genes.

Dataset Information

Identification of novel breast cancer susceptibility loci in meta-analyses conducted among Asian and European descendants.

Publications

Identification of novel breast cancer susceptibility loci in meta-analyses conducted among Asian and European descendants.

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