Population stratification and genetic association studies in South Asia

Population stratification and its influence on genetic association studies is a controversial topic. Although it has been suggested that stratification is unlikely to bias the results of association studies conducted in developed countries, convincing contrary empirical evidence has been published. However, it is in populations where historical ethnic, religious and language barriers exist that community subdivisions will predictably exert greatest genetic effect, and influence the organization of association studies. In many of the populations of the Indian sub-continent, these basic population divisions are compounded by a strict tradition of intra-community marriage and by marriage between close biological relatives. Data on the very significant levels of genetic diversity that characterize the populations of India and Pakistan, with some 50,000-60,000 caste and non-caste communities in India, and average first cousin marriage rates of 40%-50% in Pakistan, are presented and discussed. Under these circumstances, failure to explicitly control for caste/biraderi membership and the presence of consanguinity could seriously jeopardize, and may totally invalidate, the results of association/case control studies and clinical trials

The impact of consanguinity on neonatal and infant health

Marriage between biological relatives is widely popular in many parts of the world, with over 1000 million people living in countries where 20–50+% of unions are contracted between couples related as second cousins or closer. Consanguinity is, however, a controversial topic, in part due to public misunderstanding, complicated by often exaggerated past estimates of the adverse health outcomes. While some consanguineous couples are at high risk of conceiving a child with a genetic disorder, they are a small minority. Thus a multi-population meta-analysis has indicated an excess infant death rate of 1.1% in the progeny of first cousins, and even this figure may be compromised by inadequate control for non-genetic variables. The benefits as well as the disadvantages of consanguineous marriage are assessed and discussed, with specific consideration given to the health of migrant communities in Western countries, among whom first cousin marriage remains preferential

Human population structure, genome autozygosity and human health

A major transition in human population structure is currently under way, moving from a historical metapopulation, comprising small and mainly rural endogamous communities, to large and increasingly panmictic urban populations. This process is predicted to increase outbreeding, and preliminary data from genomic surveys have helped to quantify the potential magnitude of the effects. Population genetic trends of this nature should result in a reduced burden of recessive disorders, and have a favourable impact on complex diseases influenced by partially recessive genetic variants of smaller effect. The overall outcome is expected to be beneficial for a range of traits associated with human health and disease that show dominance variance

Delivering genetic education and genetic counseling for rare diseases in rural Brazil

Brazil is the largest country in Latin America, with an ethnically diverse, Portuguese-speaking and predominantly Roman Catholic population of some 194 million. Universal health care is provided under the Federal Unified Health System (Sistema Único de Saúde) but, as in many other middle and low income countries, access to medical genetics services is limited in rural and remote regions of the country. Since there is no formally recognized Genetic Counseling profession, genetic counseling is provided by physicians, trained either in medical genetics or a related clinical discipline. A comprehensive medical genetics program has been established in Monte Santo, an inland rural community located in the state of Bahia in Northeast Brazil, with high prevalences of a number of autosomal recessive genetic disorders, including non-syndromic deafness, phenyketonuria, congenital hypothyroidism and mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). Genetic education, counseling and treatment are locally provided, with a neonatal screening program for MPSVI currently under trial

Endogamy, consanguinity and the health implications of changing marital choices

YesThe biraderi (brotherhood) is a long-established, widely prevalent dimension of social stratification in Pakistani communities worldwide. Alongside consanguinity, it offers a route for cementing social solidarities and so has strong sociobiological significance. A detailed breakdown of biraderi affiliation among participants in an ongoing birth cohort study in the Northern English city of Bradford is presented. There is historical resilience of intra-biraderi marriage, but with a secular decline in prevalence across all biraderi and considerable reductions in some. While a majority of marriages in all biraderi are consanguineous the prevalence varies, ranging from over 80% to under 60%. In consanguineous unions, first cousin marriages account for more than 50% in five of the 15 biraderi and >40% in six others. Within-biraderi marriage and consanguinity enhance genetic stratification, thereby increasing rates of genomic homozygosity and the increased expression of recessive genetic disorders. The trends we report constitute putative signals of generational change in the marital choices in this community.Wellcome Trus

Design of a framework for the deployment of collaborative independent rare disease-centric registries: Gaucher disease registry model

Orphan drug clinical trials often are adversely affected by a lack of high quality treatment efficacy data that can be reliably compared across large patient cohorts derived from multiple governmental and country jurisdictions. It is critical that these patient data be captured with limited corporate involvement. For some time, there have been calls to develop collaborative, non-proprietary, patient-centric registries for post-market surveillance of aspects related to orphan drug efficacy. There is an urgent need for the development and sustainable deployment of these ‘independent’ registries that can capture comprehensive clinical, genetic and therapeutic information on patients with rare diseases. We therefore extended an open-source registry platform, the Rare Disease Registry Framework (RDRF) to establish an Independent Rare Disease Registry (IRDR). We engaged with an established rare disease community for Gaucher disease to determine system requirements, methods of data capture, consent, and reporting. A non-proprietary IRDR model is presented that can serve as autonomous data repository, but more importantly ensures that the relevant data can be made available to appropriate stakeholders in a secure, timely and efficient manner to improve clinical decision-making and the lives of those with a rare diseas

Consanguinity and pregnancy outcomes in a multi-ethnic, metropolitan European population

Objective: The aim of the present study was to assess the risk of major anomalies in the offspring of consanguineous couples, including data on the prenatal situation. Methods: Over 20years (1993-2012), 35391 fetuses were examined by prenatal sonography. In 675 cases (1.9%), parents were consanguineous, with 307 couples (45.5%) related as first cousins, 368 couples (54.5%) beyond first cousins. Detailed information was retrieved on 31710 (89.6%) fetuses, (consanguineous 568: 1.8%). Results: Overall prevalence of major anomalies among fetuses with non-consanguineous parents was 2.9% (consanguineous, 10.9%; first cousins, 12.4%; beyond first cousins, 6.5%). Adjusting the overall numbers for cases having been referred because of a previous index case, the prevalences were 2.8% (non-consanguineous) and 6.1% (consanguineous) (first cousin, 8.5%; beyond first cousin, 3.9%). Further adjustment for differential rates of trisomic pregnancies indicated 2.0%/5.9% congenital anomalies (non-consanguineous/consanguineous groups), that is, a consanguinity-associated excess of 3.9%, 6.1% in first cousin progeny and 1.9% beyond first cousin. Conclusions: The prevalence of major fetal anomalies associated with consanguinity is higher than in evaluations based only on postnatal life. It is important that this information is made available in genetic counselling programmes, especially in multi-ethnic and multi-religious communities, to enable couples to make informed decisions

Design of a framework for the deployment of collaborative independent rare disease-centric registries: Gaucher disease registry model

Orphan drug clinical trials often are adversely affected by a lack of high quality treatment efficacy data that can be reliably compared across large patient cohorts derived from multiple governmental and country jurisdictions. It is critical that these patient data be captured with limited corporate involvement. For some time, there have been calls to develop collaborative, non-proprietary, patient-centric registries for post-market surveillance of aspects related to orphan drug efficacy. There is an urgent need for the development and sustainable deployment of these ‘independent’ registries that can capture comprehensive clinical, genetic and therapeutic information on patients with rare diseases. We therefore extended an open-source registry platform, the Rare Disease Registry Framework (RDRF) to establish an Independent Rare Disease Registry (IRDR). We engaged with an established rare disease community for Gaucher disease to determine system requirements, methods of data capture, consent, and reporting. A non-proprietary IRDR model is presented that can serve as autonomous data repository, but more importantly ensures that the relevant data can be made available to appropriate stakeholders in a secure, timely and efficient manner to improve clinical decision-making and the lives of those with a rare disease

Profiling Plasma Peptides for the Identification of Potential Ageing Biomarkers in Chinese Han Adults

Advancing age is associated with cardiovascular disease, diabetes mellitus and cancer, and shows significant inter-individual variability. To identify ageing-related biomarkers we performed a proteomic analysis on 1890 Chinese Han individuals, 1136 males and 754 females, aged 18 to 82 years, using weak cation exchange magnetic bead based MALDI-TOF-MS analysis. The study identified 44 peptides which varied in concentration in different age groups. In particular, apolipoprotein A-I (ApoA1) concentration gradually increased between 18 to 50 years of age, the levels of fibrinogen alpha (FGA) decreased over the same age span, while albumin (ALB) was significantly degraded in middle-aged individuals. In addition, the plasma peptide profiles of FGA and four other unidentified proteins were found to be gender-dependent. Plasma proteins such as FGA, ALB and ApoA1 are significantly correlated with age in the Chinese Han population and could be employed as indicative ageingrelated biomarkers

Rare single gene disorders:estimating baseline prevalence and outcomes worldwide

As child mortality rates overall are decreasing, non-communicable conditions, such as genetic disorders, constitute an increasing proportion of child mortality, morbidity and disability. To date, policy and public health programmes have focused on common genetic disorders. Rare single gene disorders are an important source of morbidity and premature mortality for affected families. When considered collectively, they account for an important public health burden, which is frequently under-recognised. To document the collective frequency and health burden of rare single gene disorders, it is necessary to aggregate them into large manageable groupings and take account of their family implications, effective interventions and service needs. Here, we present an approach to estimate the burden of these conditions up to 5 years of age in settings without empirical data. This approaches uses population-level demographic data, combined with assumptions based on empirical data from settings with data available, to provide population-level estimates which programmes and policy-makers when planning services can use