Biological basis of extensive pleiotropy between blood traits and cancer risk.

The immune system has a central role in preventing carcinogenesis. Alteration of systemic immune cell levels may increase cancer risk. However, the extent to which common genetic variation influences blood traits and cancer risk remains largely undetermined. Here, we identify pleiotropic variants and predict their underlying molecular and cellular alterations. Multivariate Cox regression was used to evaluate associations between blood traits and cancer diagnosis in cases in the UK Biobank. Shared genetic variants were identified from the summary statistics of the genome-wide association studies of 27 blood traits and 27 cancer types and subtypes, applying the conditional/conjunctional false-discovery rate approach. Analysis of genomic positions, expression quantitative trait loci, enhancers, regulatory marks, functionally defined gene sets, and bulk- and single-cell expression profiles predicted the biological impact of pleiotropic variants. Plasma small RNAs were sequenced to assess association with cancer diagnosis. The study identified 4093 common genetic variants, involving 1248 gene loci, that contributed to blood-cancer pleiotropism. Genomic hotspots of pleiotropism include chromosomal regions 5p15-TERT and 6p21-HLA. Genes whose products are involved in regulating telomere length are found to be enriched in pleiotropic variants. Pleiotropic gene candidates are frequently linked to transcriptional programs that regulate hematopoiesis and define progenitor cell states of immune system development. Perturbation of the myeloid lineage is indicated by pleiotropic associations with defined master regulators and cell alterations. Eosinophil count is inversely associated with cancer risk. A high frequency of pleiotropic associations is also centered on the regulation of small noncoding Y-RNAs. Predicted pleiotropic Y-RNAs show specific regulatory marks and are overabundant in the normal tissue and blood of cancer patients. Analysis of plasma small RNAs in women who developed breast cancer indicates there is an overabundance of Y-RNA preceding neoplasm diagnosis. This study reveals extensive pleiotropism between blood traits and cancer risk. Pleiotropism is linked to factors and processes involved in hematopoietic development and immune system function, including components of the major histocompatibility complexes, and regulators of telomere length and myeloid lineage. Deregulation of Y-RNAs is also associated with pleiotropism. Overexpression of these elements might indicate increased cancer risk.

Pardo-Cea MA ，Farré X ，Esteve A ，Palade J ，Espín R ，Mateo F ，Alsop E ，Alorda M ，Blay N ，Baiges A ，Shabbir A ，Comellas F ，Gómez A ，Arnan M ，Teulé A ，Salinas M ，Berrocal L ，Brunet J ，Rofes P ，Lázaro C ，Conesa M ，Rojas JJ ，Velten L ，Fendler W ，Smyczynska U ，Chowdhury D ，Zeng Y ，He HH ，Li R ，Van Keuren-Jensen K ，de Cid R ，Pujana MA ... -  《Genome Medicine》

Genetic colocalization atlas points to common regulatory sites and genes for hematopoietic traits and hematopoietic contributions to disease phenotypes.

Thom CS ，Voight BF 《BMC Medical Genomics》

Multivariate Genome-wide Association Analysis of a Cytokine Network Reveals Variants with Widespread Immune, Haematological, and Cardiometabolic Pleiotropy.

Cytokines are essential regulatory components of the immune system, and their aberrant levels have been linked to many disease states. Despite increasing evidence that cytokines operate in concert, many of the physiological interactions between cytokines, and the shared genetic architecture that underlies them, remain unknown. Here, we aimed to identify and characterize genetic variants with pleiotropic effects on cytokines. Using three population-based cohorts (n = 9,263), we performed multivariate genome-wide association studies (GWAS) for a correlation network of 11 circulating cytokines, then combined our results in meta-analysis. We identified a total of eight loci significantly associated with the cytokine network, of which two (PDGFRB and ABO) had not been detected previously. In addition, conditional analyses revealed a further four secondary signals at three known cytokine loci. Integration, through the use of Bayesian colocalization analysis, of publicly available GWAS summary statistics with the cytokine network associations revealed shared causal variants between the eight cytokine loci and other traits; in particular, cytokine network variants at the ABO, SERPINE2, and ZFPM2 loci showed pleiotropic effects on the production of immune-related proteins, on metabolic traits such as lipoprotein and lipid levels, on blood-cell-related traits such as platelet count, and on disease traits such as coronary artery disease and type 2 diabetes.

Nath AP ，Ritchie SC ，Grinberg NF ，Tang HH ，Huang QQ ，Teo SM ，Ahola-Olli AV ，Würtz P ，Havulinna AS ，Santalahti K ，Pitkänen N ，Lehtimäki T ，Kähönen M ，Lyytikäinen LP ，Raitoharju E ，Seppälä I ，Sarin AP ，Ripatti S ，Palotie A ，Perola M ，Viikari JS ，Jalkanen S ，Maksimow M ，Salmi M ，Wallace C ，Raitakari OT ，Salomaa V ，Abraham G ，Kettunen J ，Inouye M ... -  《-》

Cross-cancer pleiotropic analysis identifies three novel genetic risk loci for colorectal cancer.

To understand the shared genetic basis between colorectal cancer (CRC) and other cancers and identify potential pleiotropic loci for compensating the missing genetic heritability of CRC. We conducted a systematic genome-wide pleiotropy scan to appraise associations between cancer-related genetic variants and CRC risk among European populations. Single nucleotide polymorphism (SNP)-set analysis was performed using data from the UK Biobank and the Study of Colorectal Cancer in Scotland (10 039 CRC cases and 30 277 controls) to evaluate the overlapped genetic regions for susceptibility of CRC and other cancers. The variant-level pleiotropic associations between CRC and other cancers were examined by CRC genome-wide association study meta-analysis and the pleiotropic analysis under composite null hypothesis (PLACO) pleiotropy test. Gene-based, co-expression and pathway enrichment analyses were performed to explore potential shared biological pathways. The interaction between novel genetic variants and common environmental factors was further examined for their effects on CRC. Genome-wide pleiotropic analysis identified three novel SNPs (rs2230469, rs9277378 and rs143190905) and three mapped genes (PIP4K2A, HLA-DPB1 and RTEL1) to be associated with CRC. These genetic variants were significant expressions quantitative trait loci in colon tissue, influencing the expression of their mapped genes. Significant interactions of PIP4K2A and HLA-DPB1 with environmental factors, including smoking and alcohol drinking, were observed. All mapped genes and their co-expressed genes were significantly enriched in pathways involved in carcinogenesis. Our findings provide an important insight into the shared genetic basis between CRC and other cancers. We revealed several novel CRC susceptibility loci to help understand the genetic architecture of CRC.

Sun J ，Wang L ，Zhou X ，Hu L ，Yuan S ，Bian Z ，Chen J ，Zhu Y ，Farrington SM ，Campbell H ，Ding K ，Zhang D ，Dunlop MG ，Theodoratou E ，Li X ... -  《-》

Role of the Gut-Brain Axis in the Shared Genetic Etiology Between Gastrointestinal Tract Diseases and Psychiatric Disorders: A Genome-Wide Pleiotropic Analysis.

Gong W ，Guo P ，Li Y ，Liu L ，Yan R ，Liu S ，Wang S ，Xue F ，Zhou X ，Yuan Z ... -  《-》