Do consanguineous parents of a child affected by an autosomal recessive disease have more DNA identical-by-descent than similarly-related parents with healthy offspring? Design of a case-control study

<p>Abstract</p> <p>Background</p> <p>The offspring of consanguineous relations have an increased risk of congenital/genetic disorders and early mortality. Consanguineous couples and their offspring account for approximately 10% of the global population. The increased risk for congenital/genetic disorders is most marked for autosomal recessive disorders and depends on the degree of relatedness of the parents. For children of first cousins the increased risk is 2-4%. For individual couples, however, the extra risk can vary from zero to 25% or higher, with only a minority of these couples having an increased risk of at least 25%. It is currently not possible to differentiate between high-and low-risk couples. The quantity of DNA identical-by-descent between couples with the same degree of relatedness shows a remarkable variation. Here we hypothesize that consanguineous partners with children affected by an autosomal recessive disease have more DNA identical-by-descent than similarly-related partners who have only healthy children. The aim of the study is thus to establish whether the amount of DNA identical-by-descent in consanguineous parents of children with an autosomal recessive disease is indeed different from its proportion in consanguineous parents who have healthy children only.</p> <p>Methods/Design</p> <p>This project is designed as a case-control study. Cases are defined as consanguineous couples with one or more children with an autosomal recessive disorder and controls as consanguineous couples with at least three healthy children and no affected child. We aim to include 100 case couples and 100 control couples. Control couples are matched by restricting the search to the same family, clan or ethnic origin as the case couple. Genome-wide SNP arrays will be used to test our hypothesis.</p> <p>Discussion</p> <p>This study contains a new approach to risk assessment in consanguineous couples. There is no previous study on the amount of DNA identical-by-descent in consanguineous parents of affected children compared to the consanguineous parents of healthy children. If our hypothesis proves to be correct, further studies are needed to obtain different risk figure estimates for the different proportions of DNA identical-by-descent. With more precise information about their risk status, empowerment of couples can be improved when making reproductive decisions.</p

Multivariate Genetic Structure of Externalizing Behavior and Structural Brain Development in a Longitudinal Adolescent Twin Sample

Externalizing behavior in its more extreme form is often considered a problem to the individual, their families, teachers, and society as a whole. Several brain structures have been linked to externalizing behavior and such associations may arise if the (co)development of externalizing behavior and brain structures share the same genetic and/or environmental factor(s). We assessed externalizing behavior with the Child Behavior Checklist and Youth Self Report, and the brain volumes and white matter integrity (fractional anisotropy [FA] and mean diffusivity [MD]) with magnetic resonance imaging in the BrainSCALE cohort, which consisted of twins and their older siblings from 112 families measured longitudinally at ages 10, 13, and 18 years for the twins. Genetic covariance modeling based on the classical twin design, extended to also include siblings of twins, showed that genes influence externalizing behavior and changes therein (h2 up to 88%). More pronounced externalizing behavior was associated with higher FA (observed correlation rph up to +0.20) and lower MD (rph up to –0.20), with sizeable genetic correlations (FA ra up to +0.42; MD ra up to –0.33). The cortical gray matter (CGM; rph up to –0.20) and cerebral white matter (CWM; rph up to +0.20) volume were phenotypically but not genetically associated with externalizing behavior. These results suggest a potential mediating role for global brain structures in the display of externalizing behavior during adolescence that are both partially explained by the influence of the same genetic factor

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

Consanguineous marriages, pearls and perils: Geneva International Consanguinity Workshop Report

Approximately 1.1 billion people currently live in countries where consanguineous marriages are customary, and among them one in every three marriages is between cousins. Opinions diverge between those warning of the possible health risks to offspring and others who highlight the social benefits of consanguineous marriages. A consanguinity study group of international experts and counselors met at the Geneva International Consanguinity Workshop from May 3 2010, to May 7, 2010, to discuss the known and presumptive risks and benefits of close kin marriages and to identify important future areas for research on consanguinity. The group highlighted the importance of evidence-based counseling recommendations for consanguineous marriages and of undertaking both genomic and social research in defining the various influences and outcomes of consanguinity. Technological advances in rapid high-throughput genome sequencing and for the identification of copy number variants by comparative genomic hybridization offer a significant opportunity to identify genotype-phenotype correlations focusing on autozygosity, the hallmark of consanguinity. The ongoing strong preferential culture of close kin marriages in many societies, and among migrant communities in Western countries, merits an equivalently detailed assessment of the social and genetic benefits of consanguinity in future studies

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