Identification of four novel associations for B-cell acute lymphoblastic leukaemia risk.

There is increasing evidence for a strong inherited genetic basis of susceptibility to acute lymphoblastic leukaemia (ALL) in children. To identify new risk variants for B-cell ALL (B-ALL) we conducted a meta-analysis with four GWAS (genome-wide association studies), totalling 5321 cases and 16,666 controls of European descent. We herein describe novel risk loci for B-ALL at 9q21.31 (rs76925697, P = 2.11 × 10-8), for high-hyperdiploid ALL at 5q31.1 (rs886285, P = 1.56 × 10-8) and 6p21.31 (rs210143 in BAK1, P = 2.21 × 10-8), and ETV6-RUNX1 ALL at 17q21.32 (rs10853104 in IGF2BP1, P = 1.82 × 10-8). Particularly notable are the pleiotropic effects of the BAK1 variant on multiple haematological malignancies and specific effects of IGF2BP1 on ETV6-RUNX1 ALL evidenced by both germline and somatic genomic analyses. Integration of GWAS signals with transcriptomic/epigenomic profiling and 3D chromatin interaction data for these leukaemia risk loci suggests deregulation of B-cell development and the cell cycle as central mechanisms governing genetic susceptibility to ALL

Resisting the mantle of the monstrous feminine : women's construction and experience of premenstrual embodiment

The female reproductive body is positioned as abject, as other, as site of defciency and disease, the epitome of the ‘monstrous feminine.’ Premenstrual change in emotion, behavior or embodied sensation is positioned as a sign of madness within, necessitating restraint and control on the part of the women experiencing it (Ussher 2006). Breakdown in this control through manifestation of ‘symptoms’ is diagnosed as PMS (Premenstrual Syndrome) or PMDD (Premenstrual Dysphoric Disorder), a pathology deserving of ‘treatment.’ In this chapter, we adopt a feminist material-discursive theoretical framework to examine the role of premenstrual embodiment in relation to women’s adoption of the subject position of monstrous feminine, drawing on interviews we have conducted with women who self-diagnose as ‘PMS sufferers.’ We theorize women’s self-positioning as subjectifcation, wherein women take up cultural discourse associated with idealized femininity and the reproductive body, resulting in self-objectifcation, distress, and self-condemnation. However, women can resist negative cultural constructions of premenstrual embodiment and the subsequent self-policing. We describe the impact of women-centered psychological therapy which increases awareness of embodied change, and leads to greater acceptance of the premenstrual body and greater self-care, which serves to reduce premenstrual distress

Genome-wide association studies of cancer: current insights and future perspectives.

Genome-wide association studies (GWAS) provide an agnostic approach for investigating the genetic basis of complex diseases. In oncology, GWAS of nearly all common malignancies have been performed, and over 450 genetic variants associated with increased risks have been identified. As well as revealing novel pathways important in carcinogenesis, these studies have shown that common genetic variation contributes substantially to the heritable risk of many common cancers. The clinical application of GWAS is starting to provide opportunities for drug discovery and repositioning as well as for cancer prevention. However, deciphering the functional and biological basis of associations is challenging and is in part a barrier to fully unlocking the potential of GWAS

Fine-mapping analysis including over 254,000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes

Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development