Review article
Neurogenomics in Africa: Perspectives, progress, possibilities and priorities

https://doi.org/10.1016/j.jns.2016.05.006Get rights and content

Highlights

  • Current knowledge on neurogenetics in African populations is limited.

  • Autosomal and recessive neurological disorders exist in Africa.

  • Current insurgency suggests unique opportunities to advance genetic knowledge in Africa.

  • There is much scope for novel diagnostics, prevention and targeted treatments.

  • Stakeholder engagement and sustainable multidisciplinary capacity building is encouraged.

Abstract

The understanding of the genetic basis of neurological disorders has grown rapidly in the last two decades. Despite the genomic heterogeneity within African populations, large-scale candidate gene or linkage and exome studies are lacking. However, current knowledge on neurogenetics in African populations is limited and geographically very uneven. Isolated reports indicate the existence of autosomal dominant or recessive conditions incorporating cerebrovascular, movement, neuromuscular, seizure and motor neuron disorders in Africans. In addition, few African families with neurodegenerative disorders associated with dementia have been characterized in North, West and South Africa. The current insurgency in genomic research triggered by among others the Human Health and Heredity (H3) Africa Initiative indicates that there are unique opportunities to advance our knowledge and understanding of the influence of genomic variation on the pattern, presentations and prognosis of neurological disorders in Africa. These have enormous potential to unmask novel genes and molecular pathways germane to the neurobiology of brain disorders. It would facilitate the development of novel diagnostics, preventative and targeted treatments in the new paradigm of precision medicine. Nevertheless, it is crucial to strike a balance between effective traditional public health strategies and personalized genome based care. The translational barriers can be overcome through robust stakeholder engagement and sustainable multilevel, multigenerational and multidisciplinary capacity building and infrastructural development for genomic medicine in Africa.

Introduction

Our understanding of the genetic basis of neurological disorders has grown rapidly in the last two decades. This has been accomplished largely by the ‘positional cloning’ research paradigm that utilizes linkage studies to localize specific genes on chromosomes and the subsequent identification of causative genes by targeted screening of Mendelian neurological disorders [1], [2]. However, most neurological disorders are polygenic disorders with non–Mendelian inheritance. The clinical phenotype is often the culmination of several complex processes and interacting pathways that involve genetic, epigenetic and environmental factors [3]. As such, the exact influence of genetic factors on neurological disorders varies giving rise to differing phenotypic manifestations.

In monogenic neurological disorders e.g. Huntington's disease, spinocerebellar ataxias, patterns of inheritance which may be autosomal dominant or recessive, are easier to elucidate whereas the genetic contributions to polygenic neurological disorders such as stroke, Alzheimer's disease and the epilepsies may result from common variants with small effect sizes, rare variants with large effect sizes, or a combination of both [4]. For populations in Africa, on the one hand there are some published studies exploring the genetic underpinnings of certain neurological disorders including Parkinson's disease, age-related dementias, and spinocerebellar ataxias while on the other hand there is barely any specific genetic knowledge on stroke, rare disorders or headache syndromes (Table 1, Table 2). Moreover, virtually all the available published data among Africans were derived from linkage analysis and limited candidate gene studies with no published evidence of genome wide association studies (GWAS) or next generation sequencing approaches.

It is not clear what proportion of the burden can be attributed to genetic transmission but current estimates show Africa bears a high burden of all cause neurological disorders. By 2010, all causes of neurological, mental health and substance-use disorders including cerebrovascular diseases and pain were estimated to account for more than 29% of the global burden of disease [5], [6]. In tandem with increased life expectancy, the global burden of disease has shifted from premature death to increased years lived with disability per 100,000. By 2013, the disability-adjusted life years (DALYs) attributed to neurological disorders including cerebrovascular disease and neurogenic pain for sub-Saharan Africa alone are estimated to be 4.4% compared to 11% for all developing regions of the world [7]. The spectrum of neurological disorders encompasses childhood developmental conditions to ageing-related dementias [6], [8]. Given the origin of previous widely published reports, genetic studies on neurological studies have been carried out in only 17 countries in Africa out of 58 independent states with the currently estimated population of 1.2 billion. They have been concentrated in 4 North African countries including Morocco, Algeria, Tunisia and Egypt and 13 countries in sub-Saharan Africa including Burkina Faso, Central African Republic, Gambia, Ghana, Kenya, Mali, Malawi, Nigeria, Rwanda, Sudan, South Africa, Tanzania and Zambia (Table 1, Table 2). The expectedly high burden of neurological disease together with the substantial genomic heterogeneity of African populations [9], [10] offers a unique opportunity to identify and understand other novel genes and molecular pathways, which contribute to the neurobiology of brain disorders. This may lead to new and better detection, prevention and treatment options in people of African ancestry and possibly by extension, other global populations particularly in the new paradigm of personalized precision medicine [11], [12].

In this article, we discuss the basis of African genomic variation and provide an overview of the status of knowledge on the genetics of neurological disorders in Africa (Fig. 1). We also highlight the current genomic revolution triggered by the H3Africa Initiative [13], identify potential future gains in knowledge and suggest priorities for effective translational genomics in Africa.

Section snippets

African human genomic variation

African populations harbor the broadest genomic diversity, lowest levels and most divergent patterns of linkage disequilibrium, as well as smaller haplotype block sizes among the world's human population [9], [14]. Studies of genomic variation in Africa suggest that the present pattern of variation within and between populations is a product of several factors. These include demographic history, population structure, diversities of geographical location, language classification and different

Progress through the H3Africa Initiative

The Human Health and Heredity in Africa (H3Africa) Initiative [13], with funding support from the US National Institutes of Health (NIH) and the UK Wellcome Trust, is currently executing 24 different large–scale, disease–based projects involving 50–75,000 participants across the African continent [13]. This initiative promises to enhance our understanding of human genomic variation and unravel the genomic basis of several diseases on the continent, while facilitating genomic infrastructural

Possibilities of future gains in knowledge

Much of what is known about neurogenomics in Africa has been achieved largely through small-scale genotyping and linkage analysis studies (Fig. 1). The advent of the H3Africa Initiative has triggered a silent genomic revolution in Africa [13]. This initiative is helping to build the necessary framework for the establishment of Afrocentric, African-driven, Africa-wide consortia on brain disorders which can, in future, utilize the infrastructure and capacity currently being developed. This will

Priorities for translational genomics in Africa

Translational genomics investigates how genomic and epigenomic individuality predisposes to health and disease and how an individual's genome expresses itself at different omic levels (transcriptomics, proteomics, metabolomics, lipidomics) in response to the environment (exposome), including e.g. drugs, nutrition and physical activity [140]. This knowledge forms the basis of personalized precision medicine with solutions that can be applied in real time to maintain health and evaluate,

Search strategy and systematic review

A systematic literature search of PubMed and Medline was done with combinations of search terms, including “Africa” and “genetics” or “genomics”, with topic headings including “cerebrovascular diseases”, “stroke”, “CADASIL”, “cavernous malformations”, “aneurysm”, “ataxia”, “dystonia”, “Parkinson's disease”, “Huntington's disease”, “Alzheimer's disease”, “Lewy body dementia”, “Frontotemporal dementia”, “vascular dementia”, “vascular cognitive impairment”, “seizure disorders”, “epilepsies”,

Acknowledgment

Our work is supported by NIH Grant NIH U54HG007479-01 as part of the Human Health and Heredity in Africa (H3A) Consortium. RNK is supported by grants from the Medical Research Council UK (G1100540) and Alzheimer's Research UK (ART-PG2011-15). Some of the information described in the review was discussed at the Brain Ageing and Dementia symposium held in Nairobi, Kenya in December 2012.

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