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Large Scale Genetic Research on Neuropsychiatric Disorders in African Populations
is Needed
Shareefa Dalvie
a,b,
, Nastassja Koen
b,c
,LaramieDuncan
d,e,f
, Catherine Abbo
g
, Dickens Akena
g
, Lukoye Atwoli
h
,
Bonginkosi Chiliza
i
, Kirsten A. Donald
j
, Eugene Kinyanda
g,k
, Christine Lochner
c,i
, Sumaya Mall
b
,
Noeline Nakasujja
g
, Charles R. Newton
l,m
, Raj Ramesar
a
, Goodman Sibeko
b
, Solomon Teferra
n
,
Dan J. Stein
b,c
, Karestan C. Koenen
e,o,p
a
MRC/UCT Human Genetics Research Unit, Division of Human Genetics, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, Cape Town, South Africa
b
Department of Psychiatry and Mental Health, University of Cape Town, Observatory, Cape Town, South Africa
c
Medical Research Council (MRC) Unit on Anxiety and Stress Disorders, Cape Town, South Africa
d
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
e
Stanley Center for Psychiatric Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
f
Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
g
Department of Psychiatry, School of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda
h
Department of Mental Health, School of Medicine, Moi University College of Health Sciences, Eldoret, Kenya
i
Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, Western Cape, South Africa
j
Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, University of Cape Town,Cape Town, South Africa
k
MRC/UVRI Uganda Research Unit on AIDS, Entebbe, Uganda
l
KEMRI-Wellcome Trust Research Programme, Kili, Kenya
m
Department of Psychiatry, University of Oxford, Oxford, UK
n
Department of Psychiatry, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
o
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
p
Psychiatric and Neurodevelopmental Genetics Unit and Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA
article info
Article history:
Received 30 September 2015
Accepted 2 October 2015
Available online xxxx
Keywords:
Psychiatry
Genetics
Africa
Neuropsychiatry
In recent years there have been signicant insights into the complex
aetiologies of neurodevelopmental brain disorders. For example, neuro-
psychiatric genetics has achieved success with the identication of 108
loci for schizophrenia (Schizophrenia Working Group of the Psychiatric
Genomics Consortium, 2014). Furthermore, meta-analyses of genome-
wide association study (GWAS) results encompassing thousands of
samples have been completed for other psychiatric disorders in-
cluding attention-decit/hyperactivity disorder (ADHD), autism
EBioMedicine xxx (201 5) xxxxxx
Corresponding author.
E-mail address: dlvsha006@myuct.ac.za (S. Dalvie).
EBIOM-00323; No of Pages 3
spectrum disorders, bipolar disorder, and major depressive disor-
der. However, published results on neuropsychiatric disorders
have thus far predominantly included samples of European an-
cestry. In Fig. 1a, we compare world ancestry to the ancestry of in-
dividuals in the largest psychiatric GWAS meta-analyses published
prior to 2015 (Total N = 121,985). The lack of African samples in
the meta-analyses so clearly depicted here, raises concern that
Africa will be left behind in terms of neuropsychiatric genetic re-
search and subsequent treatment innovation.
There is biological rationale for conducting genetic research in
African populations. It has been shown that modern humans originated
in Africa and subsequently migrated to other parts of the world
(Campbell and Tishkoff, 2008). As the cradle of humanity, Africa and
its indigenous populations are avaluable resource when it comes to ge-
netic research. Modern African genomes are characterised by a unique
pattern of variation as a result of migration and admixture in earlier
generations as well as recombination, natural selection and mutation.
With an increase in allelic diversity and shorter segments of linkage dis-
equilibrium, African genomes hold informative alleles which are useful
for ne mapping of disease causing alleles (Campbell and Tishkoff,
2008). However, there is limited knowledge on African-specic func-
tional variants highlighting the need to investigate African population
groups, particularly for neuropsychiatric disorders.
As genetic ndings are translated into intervention, genetic research
focused solely on European populations threatens to widen the existing
http://dx.doi.org/10.1016/j.ebiom.2015.10.002
2352-3964/© 2015 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Contents lists available at ScienceDirect
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Please cite this article as: Dalvie, S., et al., Large Scale Genetic Research on Neuropsychiatric Disorders in African Populations is Needed,
EBioMedicine (2015), http://dx.doi.org/10.1016/j.ebiom.2015.10.002
large disparity between Africa andthe rest of the world in mental health
treatment. The vast majority of work is being conducted in high-income
settings, such as the U.S.A. and Denmark, with a large proportion of sub-
jects of Northern European ancestry (Fig. 1a). To date, there have been
no large-scale studies on the genetics of neuropsychiatric disorders in
African populations. The few studies that have been conducted have
been on small samples, typically under a thousand in number (Kolassa
et al., 2010). Recent successes in studies of schizophrenia have demon-
strated that very large scale meta-analysis is necessary to identify
genetic variants associated with neuropsychiatric disorders. Without
engaging African scientists and physicians and performing studies of
African populations, there is a signicant risk that the recent advances
in neuropsychiatric genetics will result in a widening of the massive
research and treatment gaps between Africa and the rest of the world.
Indeed, one of the aims of the movement for global mental health is to
decrease inequality in mental health outcomes particularly for low-
and middle-income countries (Patel, 2012), typical of much of the
African continent.
Researchers in Africa are faced with a number of unique challenges.
Research funding is scarce, and African scientists are often not eligible
for training mechanisms offered by the National Institutes of Health
and other funding agencies. Much of the funding that is available focus-
es on public mental health issues rather than on neuroscience or the
integration of neuroscience with public mental health (Stein et al.,
2015). Also, many African countries lack the infrastructure required to
conduct large-scale neuropsychiatric genetics research, e.g. refrigera-
tion for blood samples and cloud-based technology for phenotypic
data collection. Furthermore, there is a shortage of highly skilled genet-
icists and clinician-scientists, highlighting the need for training and ca-
pacity building in African countries. In particular, clinicians need to
develop culturally appropriate tools for the diagnosis and phenotyping
of these disorders. There are also several ethical considerations, espe-
cially in the context ofcollaborative global health partnerships between
high and low to middle income countries. These include ethical issues
about informed consent; poverty, low literacy, language barriers and
poor access to healthcare (De Vries et al., 2011). Additionally, fairness
in international collaboration needs to be ensured, with researchers
having equal access to data, and intellectual property rights adequately
addressed. When working with individuals with mental health prob-
lems, in countries with a lack or paucity of mental health prioritization,
these types of challenges are exacerbated. Lastly, existing microarray
panels may not adequately capture common haplotypes in African pop-
ulations. This highlights the need for genotyping chips which contain
tag single nucleotide polymorphisms (SNPs) that are able to encapsu-
late common variation across African population groups (Gurdasani
et al., 2015).
Despite these challenges, a number of emerging studies may hold
promise for future neurogenetics research in Africa. For example, the
Drakenstein Child Health Study (http://www.paediatrics.uct.ac.za/
scah/dclhs) is a multidisciplinary South African birth cohort study in-
vestigating genetic and environmental risk factors for common mental
disorders. The cohort consists of 1200 motherchild pairs and a subset
of these individuals has already been genotyped with a genome-wide
panel of markers shown to be relevant to psychiatric disorders. The
post-traumatic stress disorder (PTSD) subgroup of the multi-national
Psychiatric Genomics Consortium (PGC) (http://www.med.unc.edu/
pgc) aims to carry out large-scale GWASs and has included South
African samples in their analyses. To date, the PTSD-PGC group has ac-
cess to approximately 20,000 samples from study sites. As depicted by
Fig. 1b, the ancestry of individuals in the PGC-PTSD studies is more
diverse than large psychiatric GWAS in general. The Enhancing
Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Network
(http://enigma.ini.usc.edu/about-2/), a consortium investigating brain
structure, function and disease using brain imaging and genomics, has
also included samples from South Africa. This consortium comprises
70 institutions world-wide and consists of different disease working
groups including those for schizophrenia, bipolar disorder and PTSD, re-
spectively. Lastly, the Human Heredity and Health in Africa (H3Africa)
(http://h3africa.org/) initiative seeks to improve health in African
populations by investigating genomic and environmental factors
contributing to common disease. This initiative includes a study investi-
gating the genetic basis of schizophrenia in the southern African Xhosa-
speaking population group. Using exome-sequencing and by investigat-
ing genome-wide copy-number variation, this study aims to identify
genes associated with schizophrenia. Similarly, an initiative tentatively
called the Neuropsychiatric Genetics in African Populations (Neuro-
GAP), by the Stanley Center for Psychiatric Research of the Broad
Institute of MIT and Harvard University, in collaboration with the Uni-
versity of Cape Town and a number of other African institutions, aims
to improve and achieve equity in mental health by expanding the infra-
structure and research ndings from large-scale psychiatric genetic
epidemiology to Africa. This will be achieved by enhancing neuropsy-
chiatric genetic research capacity in Africa through the training of scien-
tists, conducting very large-scale samplecollection and analysis through
supporting the development of locally ledresearch programmes in neu-
ropsychiatric genetics and leveraging unique opportunities in popula-
tion genetics.
In conclusion, whilethere is a clear need for further workin elucidat-
ing the genetics of neuropsychiatric disorders in African populations,
Fig. 1. Proportion of world population groups in psychiatric GWAS. (a) Proportion inves-
tigated in the largest meta-analyses published prior to 2015 for four leading psychiatric
disorders (schizophrenia (Schizophrenia Working Gr oup of the Psychiatric Genomic s
Consortium, 2014), bipolar disorder (Psychiatric GWAS Consortium Bipolar Disorder
Working Group, 2011), major depressive disorder (Ripke et al., 2013), and ADHD (Neale
et al., 2010); total N = 121,985). (b) Proportion investigated in PGC-PTSD studies (total
N = 20,468).
World population data from http://en.wikipedia.org/w/index.php?title=World_
population&oldid=648649676.
2S. Dalvie et al. / EBioMedicine xxx (2015) xxxxxx
Please cite this article as: Dalvie, S., et al., Large Scale Genetic Research on Neuropsychiatric Disorders in African Populations is Needed,
EBioMedicine (2015), http://dx.doi.org/10.1016/j.ebiom.2015.10.002
several challenges will rst need to be tackled. An effective local net-
work of neurogenetic researchers needs to be established in order to
discover genetic variation predisposing to neuropsychiatric disorders.
This research needs to avoid prior pitfalls of safari researchby engag-
ing and training African scientists and physicians to improve phenotyp-
ing and perform studies of African populations to ensure long-term
capacity to translate genetic ndings in a way that will benet African
peoples.
Conicts of Interest
Dan Stein has received research grants and/or consultancy honoraria
from AMBRF, Biocodex, Cipla, Lundbeck, National Responsible Gambling
Foundation, Novartis, Servier, and Sun.
Funding Source
The authors are members of the Neuropsychiatric Genetics in
African Populations (Neuro-GAP) consortium. Dan Stein is funded by
the Medical Research Council of South Africa.
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... In further support of this call to action, it has been recognized that African genomes contain more diversity than any other population group, having uniquely shorter haplotype blocks with more variants per individual (Genomes Project Consortium, 2015). As a result, studies of African populations could uncover additional pathogenic variants and identify novel disease-associated loci (Dalvie et al., 2015). Therefore, future African neuropsychiatric research may yield genomic insights into the risk, resilience (Wojcik et al., 2019), and treatment of psychiatric disorders, advancing precision medicine across global populations (Dalvie et al., 2015). ...
... As a result, studies of African populations could uncover additional pathogenic variants and identify novel disease-associated loci (Dalvie et al., 2015). Therefore, future African neuropsychiatric research may yield genomic insights into the risk, resilience (Wojcik et al., 2019), and treatment of psychiatric disorders, advancing precision medicine across global populations (Dalvie et al., 2015). ...
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