Whole-genome sequencing of multiple myeloma reveals oncogenic pathways are targeted somatically through multiple mechanisms.

Multiple myeloma (MM) is a biologically heterogeneous malignancy, however, the mechanisms underlying this complexity are incompletely understood. We report an analysis of the whole-genome sequencing of 765 MM patients from CoMMpass. By employing promoter capture Hi-C in naïve B-cells, we identify cis-regulatory elements (CREs) that represent a highly enriched subset of the non-coding genome in which to search for driver mutations. We identify regulatory regions whose mutation significantly alters the expression of genes as candidate non-coding drivers, including copy number variation (CNV) at CREs of MYC and single-nucleotide variants (SNVs) in a PAX5 enhancer. To better inform the interplay between non-coding driver mutations with other driver mechanisms, and their respective roles in oncogenic pathways, we extended our analysis identifying coding drivers in 40 genes, including 11 novel candidates. We demonstrate the same pathways can be targeted by coding and non-coding mutations; exemplified by IRF4 and PRDM1, along with BCL6 and PAX5, genes that are central to plasma cell differentiation. This study reveals new insights into the complex genetic alterations driving MM development and an enhanced understanding of oncogenic pathways

Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention

Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type IIA muscle fibers, and possibly protection from exercise-induced muscle damage. Finally, Mendelian randomization analyses show that beneficial effects of lower LST and higher MVPA on several risk factors and diseases are mediated or confounded by body mass index (BMI). Our results provide insights into physical activity mechanisms and its role in disease prevention.Multi-ancestry meta-analyses of genome-wide association studies for self-reported physical activity during leisure time, leisure screen time, sedentary commuting and sedentary behavior at work identify 99 loci associated with at least one of these traits

Beyond equilibrium climate sensitivity

ISSN:1752-0908ISSN:1752-089

Multiple myeloma clonal evolution in homogeneously treated patients

International audienc

Parental and offspring contribution of genetic markers of adult blood pressure in early life: The FAMILY study

<div><p>Previous genome wide association studies (GWAS) identified associations of multiple common variants with diastolic and systolic blood pressure traits in adults. However, the contribution of these loci to variations of blood pressure in early life is unclear. We assessed the child and parental contributions of 33 GWAS single-nucleotide polymorphisms (SNPs) for blood pressure in 1,525 participants (515 children, 406 mothers and 237 fathers) of the Family Atherosclerosis Monitoring In early life (FAMILY) study followed-up for 5 years. Two genotype scores for systolic (29 SNPs) and diastolic (24 SNPs) blood pressure were built. Linear mixed-effect regressions showed significant association between rs1378942 in <i>CSK</i> and systolic blood pressure (β = 0.98±0.46, <i>P</i> = 3.4×10⁻²). The child genotype scores for diastolic and systolic blood pressure were not associated in children. Nominally significant parental genetic effects were found between the SNPs rs11191548 (<i>CYP17A1</i>) (paternal, β = 2.78±1.49, <i>P</i> = 6.1×10⁻² for SBP and β = 3.60±1.24, <i>P</i> = 3.7×10⁻³ for DBP), rs17367504 (<i>MTHFR</i>) (paternal, β = 2.42±0.93, <i>P</i> = 9.3×10⁻³ for SBP and β = 1.89±0.80, <i>P</i> = 1.8×10⁻² for DBP and maternal, β = -1.32±0.60, <i>P</i> = 2.9×10⁻² and β = -1.97±0.77, <i>P</i> = 1.0×10⁻², for SBP and DBP respectively) and child blood pressure. Our study supports the view that adult GWAS loci have a limited impact on blood pressure during the five first years of life. The parental genetic effects observed on blood pressure in children may suggest epigenetic mechanisms in the transmission of the risk of hypertension. Further replication is needed to confirm our results.</p></div

Summary of the significant results using mixed-effect regressions.

<p>Summary of the significant results using mixed-effect regressions.</p

Phenotypic characteristics of the studied population.

<p>Phenotypic characteristics of the studied population.</p