Allelic variation and haplotype structure of the dopamine receptor gene DRD2 in nine Indian populations.

Abstract

The human dopaminergic system is a significant focal point of study in the fields of neuropsychiatry and pharmacology, plus it is also a promising nuclear DNA marker in studies of human genome diversity. In this study, we assayed six polymorphic markers in the dopamine D2 receptor gene (DRD2) in 482 unrelated individuals from nine ethnic populations of India. Our results demonstrate that the six markers are highly polymorphic in all populations and the constructed haplotypes show a high level of heterozygosity. Out of the eight possible three-site haplotypes, all populations commonly shared only three haplotypes. The haplotypes exhibited fairly high frequencies across multiple populations; Kurumba population showed all eight three-site haplotypes. The ancestral haplotype (B2-D2-Al) was observed at high frequency only in the Siddi population. Haplotypes based on all six markers revealed 16 haplotypes, out of which only 6 are most common with a frequency of greater than 5% in at least one of the nine populations. But only three haplotypes were shared by all nine populations with the cumulative frequency ranging from 80.8% (Kurumba) to 96.6% (Onge). Great variation in levels of linkage disequilibrium (LD) was detected, ranging from complete LD in the Badaga to virtually no LD in the Siddi. This range of LD likely reflects different population histories, such as African ancestry in the Siddi and recent founding events in the population isolates, Badaga and Kota.

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Allelic variation and haplotype structure of the Dopamine receptor gene
DRD2 in 9 Indian populations
Journal:Genetic Testing
Manuscript ID:draft
Manuscript Type:Original Articles
Date Submitted by the
Author:
n/a
Complete List of Authors:Lakkakula, Bhaskar; Centre for cellular and molecular biology
Thangaraj, Kumarasamy; Centre for cellular and molecular biology
CJ, Mulligan; University of Florida, Department of Anthropology
Alahari, Pararao; Sri Venkateswara University, Anthropology
G, Pardhasaradhi; Centre for cellular and molecular biology
K, Praveen Kumar; Centre for cellular and molecular biology
M, Shah; Centre for cellular and molecular biology
Bonala, Sabeera; Centre for cellular and molecular biology
Alla, Reddy; Centre for cellular and molecular biology
Lalji, Singh; Centre for cellular and molecular biology
Vadlamudi, Rao; Anthropological Survey of India
Keyword:Disease, DNA Testing
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*Corresponding Author
Dr. V. R. Rao
Director-In-Charge
Anthropological Survey of India
27- Jawaharlal Nehru Road.
Kolkata-700 016
India
Phone: +91-3322861796
Fax: +91-3322861685
Email: drraovr@yahoo.com
Allelic variation and haplotype structure of the Dopamine receptor
gene DRD2 in 9 Indian populations
L. V. K. S. Bhaskar1,5, K. Thangaraj1, C. J. Mulligan2, A. Papa Rao3, G.
Pardhasaradhi1, K. Praveen Kumar1, Anish M. Shah1, B. Sabeera1, A.G. Reddy1,
Lalji Singh1and V. R. Rao4*
1Centre for Cellular and Molecular Biology, Hyderabad, India;
2Department of
Anthropology, University of Florida, Florida, USA; 3Department of Anthropology, Sri
Venkateswara University, Tirupati, India; 4Anthropological Survey of India, Kolkata,
India. 5Department of Biomedical Sciences, Sri Ramachandra University, Chennai, India.

Short title: SNPs of DRD2 gene among Indian populations
Key words: DRD2, SNP, Allelic Variation, Haplotype, Linkage Disequilibrium.

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population histories, such as African ancestry in the Siddi and recent founding events in
Abstract:
The human dopaminergic system is a significant focal point of study in the fields of
neuropsychiatry and pharmacology, plus it is also a promising nuclear DNA marker in
studies of human genome diversity. In this study, we assayed six polymorphic markers in
the dopamine D2 receptor gene (DRD2) in 482 unrelated individuals from nine ethnic
populations of India. Our results demonstrate that the six markers are highly polymorphic
in all populations and the constructed haplotypes show a high level of heterozygosity.
Out of the eight possible three-site haplotypes, all populations commonly shared only
three haplotypes. The haplotypes exibited fairly high frequencies across multiple
populatons, Kurumba population showed all 8 three-site haplotypes. The ancestral
haplotype (B2-D2-Al) was observed at high frequency only in the Siddi population.
Haplotypes based on all six markers revealed sixteen haplotypes, out of which only six
are most common with a frequency of greater than 5% in at least one of the nine
populations. But only three haplotypes were shared by all 9 populations with the
cumulative frequency range from 80.8% (Kurumba) to 96.6 (Onge). Great variation in
levels of linkage disequilibrium (LD) was detected, ranging from complete LD in the
Badaga to virtually no LD in the Siddi. This range of LD likely reflects different
the population isolates, Badaga and Kota.
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those with the A2 allele. The A1 allele is associated with high dopamine transporter
Introduction:
The human dopaminergic system is a focal point of study in the fields of neurology,
psychiatry, psychology, endocrinology as well as pharmacology. DRD2, coded for by
locus 11q23 in the human chromosome, is one receptor for the neurotransmitter
dopamine. This transmembrane receptor is a member of the rhodopsin family. To date,
the D2 dopamine receptor (DRD2) gene has been among the stronger candidate genes
implicated in alcoholism and other substance use disorders. The non-coding region of the
gene contains theree RSPs (restriction site polymorphisms), Taq1A, Taq1B, and Taq1D
and two dinucleotide STRPs (short tandem repeat polymorphisms), CA and CT repeats
(Kidd et al. 1998). The A1 allele of the DRD2 gene has been associated not only with
alcoholism, but also with other substance use disorders, including cocaine (Noble et al.
1993), nicotine (Spitz et al. 1998), opiate (Lawford et al. 2000) dependence,
polysubstance abuse (Persico et al. 1996) and obesity (Blum et al. 1996). Moreover, it
should be noted that this variant of the DRD2 gene has functional significance, as
subjects carrying the DRD2 A1 allele had a significantly decreased dopamine D2
receptor Bmax in the basal ganglia (Noble et al. 1991). Eriksson et al. (2000) reported
alcoholics with the A1 allele have lower platelet monoamino oxidase-B activity than
density in detoxified alcoholics (Laine et al. 2001).
Pairwise linkage disequilibrium (LD) generally varies with physical distance between
two markers. Different populations show different patterns of pairwise LD, and this is
reflected in different haplotype frequencies. Variation in pairwise LD is a function of the
history of human populations, and reflects the combined forces of drift, admixture, and
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using TaqI “ A” , “ B” , and “ D” sites, was confined to the five tribal populations in the
selection over evolutionary time (Zhang et al. 2003). The haplotype diversity for a
particular set of SNPs in a population reflects the sample size and the age and structure of
the population from which the sample was collected. Initial studies reported similar
haplotype frequencies and highly significant linkage disequilibrium for DRD2 in mixed
European ancestry populations using the TaqI "B" and "A" sites (Hauge et al. 1991;
O'Hara et al. 1993; Suarez et al. 1994). In another study using the same markers in U.S.
blacks, haplotype frequencies were somewhat different but linkage disequilibrium was
also highly significant (O'Hara et al. 1993). Goldman et al. (1993) reported varied allele
frequencies and significant linkage disequilibrium in three populations-Finns, American
Caucasians, and Cheyenne Amerindians. A global study using the TaqI “ A” , “ B” , and
“ D” sites and one dinucleotide STRP in 28 distinct populations showed the highest
average heterozygosity in Africa, a slightly lower average heterozygosity in Europe, and
the lowest average heterozygosities in East Asia and the Americas (Kidd et al. 1998). The
same study reports lowest LD in African populations, somewhat more in European
populations, and the maximum amount in East Asian and Amerindian populations.
Unfortunately, Indian populations, known for their rich genetic diversity were not
included in the global survey (Kidd et al. 1998). Another study on Indian populations
Nilgiri region of Tamil Nadu state (Vishwanathan et al. 2003). Here we present an
analysis on DRD2 in order to understand the evolutionary history of normal allelic
variation at this locus. In this study, we examine the haplotype frequencies and LD
relations of six DRD2 polymorphisms in nine populations belong to four linguistic
groups distributed throughout India.
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DNA polymerase (Applied Biosystems, Foster City, CA, USA). PCR amplicons were
Materials and Methods

The study population includes a total of 482 males (to allow future studies of both
mitochondrial and Y chromosomal variations) belonging to nine ethnic populations from
different geographical regions of India. Name of the population, sample size, and their
geographical location are presented in table 1 (Singh 1993; Bhasin et al. 1994) and figure
1. All subjects were apparently normal healthy volunteers and no diagnostic information
was collected. All samples were collected with written informed consent of the
participants; procedures for protection of human subjects in this study were approved by
the Institutional Ethical Review Committee of CCMB, Hyderabad. DNA was isolated
using the protocol described in Thangaraj et al. (2002).
Amplification of DRD2 gene
The DRD2 locus and location of typed markers is depicted in Fig 3. Three introns of
DRD2 were amplified using the protocol given in
http://info.med.yale.edu/genetics/kkidd/D_loci.html#DRD2 PCR was carried out in a
Gene Amp 9600 Thermal cycler (Perkin Elmer) in 10µ1 and using 1.0 U of AmpliTaq
checked on 2% agarose gel.
Sequencing of PCR amplicons
PCR amplicons (70ng) were directly sequenced using the BigDye Terminator Cycle
Sequencing Kit® (Applied Biosystems, Foster City, CA) 5PM primer (Thangaraj et al.
2003). Extended products were purified by ethanol precipitation followed by washing
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greater than 37% in all study populations with a maximum of 85% in Bhil and Todas, the
with 70% ethanol. Purified products were then dissolved in 10µ1 of 50% Hi- Di
formamide and analysed in ABI3730 automated DNA Analyser (Perkin Elmer, USA).

Statistical analysis
Each polymorphism had two co-dominant alleles. Allele frequencies were determined by
direct gene counting. The genotype distribution for each site in each sample was
evaluated for departure from Hardy-Weinberg equilibrium using the HWSIM program
(Cubells et al. 1997). Within each population, haplotype frequencies were obtained from
three-site and six-site haplotypes by summing frequencies of each relevant haplotype.
Haplotypes were estimated from phase-unknown multi-site genotypes based on a
maximum likelihood method employing an EM algorithm using Arlequin 2.0 (Schneider
et al. 2000). Linkage disequilibrium (D’ and r2) was estimated using HaploView 3.12
(Barrett et al. 2005).
Results:
Allele frequency
Individual allele frequencies are presented in figure 2A&B. The six marker systems are
polymorphic in all studied populations. The Taq1 B2 allele frequency is found to be
same was also observed for BcII2 in all populations. The Taq1 A2 site shows a similar
pattern to that of Taq1 B2 and BcII2. However, the Taq1 A2 frequencies in all
populations are slightly less than the Taq1 B2 frequencies except in Badaga and Onge,
with minimum 37% in Onge and maximum 79% in Bhil. Badaga population Taq1 A2
allele frequency is greater than the Taq1 B2 and BcII2, whereas in Onge Taq1 A2 allele
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Onge, B2-D1-A1 was present only in the Pattapu, Toda, Kota Kurumba and Siddi
is exactly equal to Taq1 B2 and BcII2. Markers rs1116313T, Taq1 D2 and rs2734835A
show a similar pattern of allele frequencies ranging from 50-90%, with maximum
frequency in Onge. The ancestral alleles (B2, D2, and A1) are all identical in sequence to
those in chimpanzees, gorillas, and orangutans (Iyengar et al. 1998). Hardy– Weinberg
proportions for each of the six DRD2 sites are presented in table 2. After Bonferroni
correction for multiple comparisons (p<0.001), all of the markers displayed Hardy-
Weinberg equilibrium in each tested population. Observed heterozygosities for individual
markers in all populations are presented in table 3. All markers showed high
heterozygosities in all populations, ranging from 0.053 to 0.690.
Haplotype frequencies:
Three site (TaqI B- TaqI D- TaqI A) haplotype frequencies in the study populations are
presented graphically in figure 3A. The majority of populations displayed highest
frequencies of the same set of three haplotypes; B2-D2-A2, B2-D1-A2 and B1-D2-A1.
Haplotype B2-D2-A1 is considered to be ancestral and was detected at high frequency
only in the Siddi (and was completely absent in the Toda), while the haplotypes B1-D1-
A2 was present only in Sahariya and Kurumba samples. Several haplotypes were only
detected in a few populations; B1-D2-A2 was present only in the Badaga, Kurumba and
populations, and B1-D1-A1 was present only in the Kurumba. Only the Kurumba tribe
shared all the eight possible three-site haplotypes with most of them occurring at a
frequency > 5%. Haplotypes based on all six markers revealed sixteen haplotypes in the
study populations. Frequencies of the six most common haplotypes, i.e. those haplotypes
that occur at a frequency of ≥5% in at least one of the nine populations, are presented in
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the Siddi and Kurumaba. Only the Badaga showed strong LD across all six markers.
figure 3B; the haplotypes occurring with lesser frequencies were considered as
‘ Residuals’ . Only three haplotypes are shared by all populations (B1-BcII1-T-D2-A-A1,
B2-BcII2-C-D1-C-A2, B2-BcII2-T-D2-A-A2) with the cumulative frequency range from
80.8% (Kurumba) to 96.6 (Onge). Two six-site haplotypes were present in only a few
populations; haplotype B1-BcII1-T-D2-A-A2 was present only in the Badaga and Onge
and haplotype B2-BcII2-C-D1-C-A1 was present only in the Kota, Kurumba, Toda and
Pattapu populations. In contrast, haplotype B2-BcII2-T-D2-A-A1 was present in all
populations except Toda (figure 3b).
Linkage disequilibrium:
We evaluated pairwise LD for all six SNPs in all nine populations (Supplementary file).
When measured by D’ , strong LD across all markers was evident in all populations.
However, using the mores stringent measure of r2(which accounts for differences in
allele frequencies), linkage disequilibrium was more fragmented across the DRD2 locus
and across different populations (Figure 4). Pairwise r2values between the TaqI B and
BcII sites (12 bases apart) showed reasonably high LD in all populations. BcII was in
significant LD with all other markers only in the Badaga population. A strong LD block
was observed among the rs111631, TaqI D and rs2734835 sites in all populations except
Discussion:
The TaqI B site is located in intron 1 of the DRD2 gene, approximately 1 kb upstream
from exon 2. Distribution of this polymorphism differs across ethnic groups; frequency of
the ancestral (B2) allele is always lower than the derived (B1) allele in all African,
European and a few East Asian populations, whereas the opposite ratio exists in all North
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are consistently high in all the populations. All six markers show high levels of
American, South American and some Asian populations (Kidd et al. 1998; Vishwanathan
et al. 2003; Luo et al. 2005). BcII site is also located in intron 1, exactly 12 bp
downstream of the TaqI B site. BcII shows the same worldwide distribution as that noted
above for TaqI B, which is not surprising given the fact that the markers are only 12bps
apart. The rs1116313 SNP site is also located in intron 1, 179 bp downstream of the TaqI
B site. The ancestral allele (T) frequencies are higher than those of derived (C) allele in
all world populations except European populations and a similar trend was also reported
for TaqI D, which is located approximately 4.5 kb downstream of the TaqI B site. For
SNP rs2734835, allele frequency data are not available, but the present study reports a
high frequency of ancestral allele (A) in all populations except the Toda and Bhil, who
belong to the Dravidian and Indo-European linguistic groups, respectively. The TaqI A
site is located 10,541 bp downstream of the termination codon of the DRD2 gene and
results in a non-synonymous change from lysine (AAG) to glutamic acid (GAG) at amino
acid 713 of the ANKK1 gene. The ancestral allele (A1) frequencies are lower than the
derived allele (A2) in all world populations except in North and South American
populations (Kidd et al. 1998). The results also showed high levels of genetic diversity
for the DRD2 locus. In the present study, the estimated levels of average heterozygosities
heterozygosity across the Indian populations, consistent with the high levels of diversity
reported in a global survey of DRD2 (Kidd et al. 1998). Furthermore, the average
heterozygosity levels were higher than in any other population studied, with the
exception of African populations (Novick et al. 1998; Relethford 1999). Population
heterozygosity tends to decrease with increasing distance from Africa - a result that is
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this haplotype is found at high frequency only in the Siddi (27.9%) is supportive of the
expected for populations leaving Africa, undergoing a bottleneck(s), and expanding into
Eurasia (Harpending and Rogers 2000). Thus, consistently high levels of diversity in the
tested Indian populations suggests that Indian populations may be more recently diverged
from African populations, relative to other studied non-African populations, and provides
support for a southern migration route out of Africa leading from the Horn of Africa,
through southern Arabia, and subsequently to India, southeast Asia and Australia (Forster
and Matsumura 2005).

Earlier studies of haplotype evolution of DRD2 (Kidd et al. 1998) have shown that the
B2, D2 and A1 alleles are the ancestral alleles, based on their presence in chimpanzees,
gorillas and orangutans. Iyengar et al. (1998) have sequenced the regions around all the
Taq1 sites in other great apes. Ignoring the sites that are polymorphic in humans, the
differences among Homo, Pan and Gorilla vary from 1.2 to 1.8% in 550– 750 bp of
homologous sequence depending on the species compared. The ancestral haplotype (B2-
D2-A1), which should exist in human evolutionary history, was infrequent in all study
populations except the Siddi (Fig.3). Similarly, Kidd et al. (1998) found that the ancestral
haplotype is common in Sub-Saharan Africans, but rare to absent elsewhere. The fact that
proposed African ancestry of the Siddi (Ramana et al. 2001; Bhaskar et al. 2007). In most
populations from America, only three three-site haplotypes (B2-D2-A1, B1-D2-A1 and
B2-D2-A2) account for the majority of all chromosomes. In Asians, East Asians and
Europeans, a fourth haplotype (B2-D1-A2) becomes quite common. These four common
haplotypes account for 78-100% of all haplotype variation in African populations,
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in non-Hispanic Caucasians. For example, TaqI A is in LD with TaqI B (Hauge et al.
between 62-98% in European populations, between 41-100% in Asian populations,
between 92-100% in East Asian populations, and between 83-100 % in Amerindian
populations. The D1 allele is primarily found on B2-A2 haplotypes whereas the D2 allele
is primarily found on A2-B2 and A1-B1 haplotypes. The B1-D2-A1 haplotype that is
observed in the present study is common in all the parts of the world except Africa.

LD refers to correlations among adjacent alleles, reflecting haplotypes descended from
single, ancestral chromosomes. Genotypes at nearby markers are not independent because
their genetic lengths are reduced by recombination and their organization may reflect
ancestral founding haplotypes. Thus, linkage disequilibrium (LD) is the nonrandom
association of alleles at different loci. Great variation in LD exists among the Indian
populations, ranging from complete LD in the Badaga to no LD in the Siddi; it is possible
that a combination of drift and selection would result in such heterogeneity (Ohta and
Kimura 1971; Tishkoff et al. 2001). Lack of significant LD in the Siddi can be explained
because of their African ancestry, which would reduce LD (Ramana et al. 2001). Higher
levels of LD detected in the Badaga and Kota populations may reflect founding events in
these population isolates (Mohlke et al. 2001). LD at DRD2 has been previously detected
1991; Kidd et al. 1998). Much of the variation observed today arose some time ago and
was present in the ancestral African population from which modern populations
descended. Our results suggest that at least some of the Indian populations have had large
effective population sizes, allowing them to maintain high levels of heterozygosity.
Acknowledgments
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dopamine beta-hydroxylase gene (DBH). Am J Med Genet 74:374-379.
This research work was supported by a grant from Department of Biotechnology,
Government of India (Project no.BT/PR3607/SPD/09/261/2003).

References:
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