A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Abstract: Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

Outcome of patients with Myelofibrosis relapsing after allogeneic stem cell transplant: a retrospective study by the Chronic Malignancies Working Party of EBMT.

Allogeneic Haematopoietic Stem Cell Transplant (allo-HSCT) remains the only curative approach for Myelofibrosis (MF). Scarce information exists in the literature on the outcome and, indeed, management of those MF patients who relapse following transplant. We hereby report on the management and outcome of 202 patients who relapsed post allo-HSCT for MF

Dynamics of Brain Structure and its Genetic Architecture over the Lifespan

Human brain structure changes throughout our lives. Altered brain growth or rates of decline are implicated in a vast range of psychiatric, developmental, and neurodegenerative diseases. While heritable, specific loci in the genome that influence these rates are largely unknown. Here, we sought to find common genetic variants that affect rates of brain growth or atrophy, in the first genome-wide association analysis of longitudinal changes in brain morphology across the lifespan. Longitudinal magnetic resonance imaging data from 10,163 individuals aged 4 to 99 years, on average 3.5 years apart, were used to compute rates of morphological change for 15 brain structures. We discovered 5 genome-wide significant loci and 15 genes associated with brain structural changes. Most individual variants exerted age-dependent effects. All identified genes are expressed in fetal and adult brain tissue, and some exhibit developmentally regulated expression across the lifespan. We demonstrate genetic overlap with depression, schizophrenia, cognitive functioning, height, body mass index and smoking. Several of the discovered loci are implicated in early brain development and point to involvement of metabolic processes. Gene-set findings also implicate immune processes in the rates of brain changes. Taken together, in the world’s largest longitudinal imaging genetics dataset we identified genetic variants that alter age-dependent brain growth and atrophy throughout our lives

Genetic variants associated with longitudinal changes in brain structure across the lifespan

Human brain structure changes throughout the lifespan. Altered brain growth or rates of decline are implicated in a vast range of psychiatric, developmental and neurodegenerative diseases. In this study, we identified common genetic variants that affect rates of brain growth or atrophy in what is, to our knowledge, the first genome-wide association meta-analysis of changes in brain morphology across the lifespan. Longitudinal magnetic resonance imaging data from 15,640 individuals were used to compute rates of change for 15 brain structures. The most robustly identified genes GPR139, DACH1 and APOE are associated with metabolic processes. We demonstrate global genetic overlap with depression, schizophrenia, cognitive functioning, insomnia, height, body mass index and smoking. Gene set findings implicate both early brain development and neurodegenerative processes in the rates of brain changes. Identifying variants involved in structural brain changes may help to determine biological pathways underlying optimal and dysfunctional brain development and aging

Dynamics of brain structure and its genetic architecture over the lifespan

Human brain structure changes throughout our lives. Altered brain growth or rates of decline are implicated in a vast range of psychiatric, developmental, and neurodegenerative diseases. While heritable, specific loci in the genome that influence these rates are largely unknown. Here, we sought to find common genetic variants that affect rates of brain growth or atrophy, in the first genome-wide association analysis of longitudinal changes in brain morphology across the lifespan. Longitudinal magnetic resonance imaging data from 10,163 individuals aged 4 to 99 years, on average 3.5 years apart, were used to compute rates of morphological change for 15 brain structures. We discovered 5 genome-wide significant loci and 15 genes associated with brain structural changes. Most individual variants exerted age-dependent effects. All identified genes are expressed in fetal and adult brain tissue, and some exhibit developmentally regulated expression across the lifespan. We demonstrate genetic overlap with depression, schizophrenia, cognitive functioning, height, body mass index and smoking. Several of the discovered loci are implicated in early brain development and point to involvement of metabolic processes. Gene-set findings also implicate immune processes in the rates of brain changes. Taken together, in the world’s largest longitudinal imaging genetics dataset we identified genetic variants that alter age-dependent brain growth and atrophy throughout our lives