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AFRICA
S41
CVJAFRICA • Volume 26, No 2, H3Africa Supplement, March/April 2015
to largely Niger-Kordofanian-speaking Yoruba and Esan from
Nigeria, Mende from Sierra Leone, Bantu-speaking Luhya from
Kenya, and Nilo-Saharan-speaking Maasai from Kenya. A
large proportion of African human genomic variation therefore
remained unexplored.
However, recent data from the African Genome Variation
project (AGVP) have provided evidence and more detailed
characterisation of African genomic diversity.
10
The AGVP
utilised dense genotypes from 1 481 individuals and whole-
genome sequences from 320 individuals across sub-Saharan
Africa. Novel evidence of complex, regionally distinct
widespread hunter–gatherer and Eurasian admixture across
sub-Saharan Africa was apparent and substantial hunter–
gatherer and Eurasian ancestry admixture of up to 23 and
50%, respectively, were found in many African populations with
detailed chronology of the timing of the admixture. For instance,
whereas the Eurasian admixture among the Yoruba occurred
7 500–10 500 years ago, it was more recent among the Fula tribe
of Gambia, occurring only about 320–780 years ago.
These admixtures provide evidence for back-to-Africa
migration, the existence of hunter–gatherer populations in
West Africa and a pattern of gene flow consistent with the
Bantu expansion. The AGVP also found new loci related to
susceptibility, pathogenesis, severity and outcome of several
diseases, including malaria, Lassa fever, trypanosomiasis,
trachoma and hypertension. For instance, they identified highly
differentiated variants within genes involved in osmoregulation
(
ATP1A1
and
AQP2
), deregulation of
AQP2
expression, and
loss-of-function mutations in
ATP1A1
have been associated with
essential and secondary hypertension, respectively.
42,43
The study
also established an efficient genotype array design capturing
common genetic variation in Africa, which would be useful for
future African genomic studies.
11,12
African American genomic variation
African Americans have mixed ancestry originating from Africa
and other continents, especially Europe. Studies have shown the
average amount of African ancestry in African Americans to
be about 80% (predominantly of western and central African
origin),
8,44,45
although there is substantial variation in the level
of African ancestry in individual African Americans, as the
proportion of African ancestry in a given individual can range
from one to 99%.
39
Genomic variation and related phenotype data on variable
traits contribute novel information useful for identifying
population-specific variants that play a role in gene function,
phenotypic adaptation and susceptibility to complex diseases,
such as stroke in Africans and populations of African descent.
The APOE
ε
4 allele, a well-studied example that contributes to
a small extent to individual and population risks of traits such
as stroke, heart disease and dementia, is found in virtually all
populations, albeit at varying rates. The frequency of homo- or
heterogeneous APO
ε
4 alleles varies across populations but
confers different attributable risks of Alzheimer’s disease; the
risk being higher among the Japanese but much lower among
people of African ancestry with higher allele frequencies. This
suggests possible intervening roles for epigenetic interactions
from certain modifier genes or some other environmental
factors.
34
Genomics of stroke and cerebrovascular risk
factors
Stroke is a complex polygenic, heterogeneous and multifactorial
disorder involving many complex mechanisms, intermediate
phenotypes and the interplay of genetic and non-genetic factors.
Evidence from twin studies, family history studies, animal models
and heritability studies of vascular risk factors and intermediate
phenotypes suggests a likely significant contribution of genetic
factors to the neurobiology and phenomenology of stroke.
1,4,46
Family history and heritability
Among individuals with a positive family history of stroke, there
is an increased risk of stroke, which may be due to expression
of genetic susceptibility, a shared environment or both.
47
In the
Family Heart study, personal and familial histories of stroke
were assessed in 3 168 individuals (probands) who were at
least 45 years old and 29 325 of their first-degree relatives. The
odds of stroke were 2.00 (1.13–3.54) for a positive paternal and
1.41 (0.80–2.50) for a positive maternal history of stroke after
adjusting for age, gender, ethnicity and presence of vascular risk
factors, and the pattern was similar between African Americans
and European Americans.
48
In a systematic review of the heritability of stroke in 53
independent studies (three twin studies, 33 case–control studies
and 17 cohort studies), it was found that monozygotic twins
were more likely to be concordant than dizygotic twins (OR,
1.65; 95% CI, 1.2–2.3;
p
=
0.003) while a positive family history
was a risk factor for stroke in both case–control (OR, 1.76; 95%
CI, 1.7–1.9;
p
<
0.00001) and cohort (OR, 1.30; 95% CI, 1.2–1.5;
p
<
0.00001) studies. Besides, positive family history was more
associated with small-vessel and large-vessel strokes.
49
Cerebrovascular risk factors
Genomic factors may contribute to the neurobiology of stroke
through their influence on established risk factors, such as
hypertension, diabetes, dyslipidaemia, obesity and cigarette
smoking or through their influence on intermediate phenotypes,
such as white matter hyperintensities (WMH) and carotid intima–
media thickness (CIMT). For instance, research evidence has shown
racial and ethnic disparities in cardiovascular and cerebrovascular
diseases, with Americans of African ancestry showing a higher
prevalence of hypertension and earlier onset, and faster and
more severe end-organ damage, including stroke.
50
Apart from
non-inherited factors such as lifestyles, health-related practices,
socio-economic profile and differential access to healthcare,
genetic factors contributed significantly to this disparity.
32
A recent genome-wide association study (GWAS) of
hypertension and blood pressure in African Americans using
the pathway-focused approach established the genome-wide
significant association of the genetic variants
PMS1, SLC24A4,
YWHA7, IPO7
and
CACANA1H
with systolic blood pressure
levels, with significant replication of some single-nucleotide
polymorphisms (SNPs) in a sample of West Africans.
51
Using
a similar approach, a more recent study has found association
between multiple variants in several genes in the adrenergic
alpha-1 receptor (ADRA1) pathway and hypertension in Yoruba
Nigerians.
52
A meta-analysis of genome-wide linkage scans for
blood pressure variation in Nigerians and African Americans