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  1. Patterns of linkage disequilibrium at PARK16 may explain variances in genetic association studies
    Li H, Teo YY, Tan EK
    Mov Disord, 2015 Sep;30(10):1335-42.
    PMID: 25758099 DOI: 10.1002/mds.26176
    Reproducing genomewide association studies findings in different populations is challenging, because the reproducibility fundamentally relies on the similar patterns of linkage disequilibrium between the unknown causal variants and the genotyped single-nucleotide polymorphisms (SNPs).
    Matched MeSH terms: Linkage Disequilibrium/genetics*
  2. Fulltext Development and Validation of a High-Density SNP Genotyping Array for African Oil Palm
    Kwong QB, Teh CK, Ong AL, Heng HY, Lee HL, Mohamed M, et al.
    Mol Plant, 2016 Aug 01;9(8):1132-1141.
    PMID: 27112659 DOI: 10.1016/j.molp.2016.04.010
    High-density single nucleotide polymorphism (SNP) genotyping arrays are powerful tools that can measure the level of genetic polymorphism within a population. To develop a whole-genome SNP array for oil palms, SNP discovery was performed using deep resequencing of eight libraries derived from 132 Elaeis guineensis and Elaeis oleifera palms belonging to 59 origins, resulting in the discovery of >3 million putative SNPs. After SNP filtering, the Illumina OP200K custom array was built with 170 860 successful probes. Phenetic clustering analysis revealed that the array could distinguish between palms of different origins in a way consistent with pedigree records. Genome-wide linkage disequilibrium declined more slowly for the commercial populations (ranging from 120 kb at r(2) = 0.43 to 146 kb at r(2) = 0.50) when compared with the semi-wild populations (19.5 kb at r(2) = 0.22). Genetic fixation mapping comparing the semi-wild and commercial population identified 321 selective sweeps. A genome-wide association study (GWAS) detected a significant peak on chromosome 2 associated with the polygenic component of the shell thickness trait (based on the trait shell-to-fruit; S/F %) in tenera palms. Testing of a genomic selection model on the same trait resulted in good prediction accuracy (r = 0.65) with 42% of the S/F % variation explained. The first high-density SNP genotyping array for oil palm has been developed and shown to be robust for use in genetic studies and with potential for developing early trait prediction to shorten the oil palm breeding cycle.
    Matched MeSH terms: Linkage Disequilibrium/genetics
  3. Genome survey and development of polymorphic microsatellite loci for Sillago sihama based on Illumina sequencing technology
    Qiu B, Fang S, Ikhwanuddin M, Wong L, Ma H
    Mol Biol Rep, 2020 Apr;47(4):3011-3017.
    PMID: 32124169 DOI: 10.1007/s11033-020-05348-z
    In this study, we first conducted a genome survey assay for Sillago sihama by Illumina sequencing platform, and then developed 15 polymorphic microsatellite loci in a wild population. A total of 129.46 Gb raw data were obtained, of which 115.07 Gb were clean data, with a sequencing depth of 179.3-folds. This genome was estimated to be 522.6 Mb in size, with the heterozygosity, repeat content and GC content being 0.63%, 21% and 44%. A total of 630,028 microsatellites were identified from the genome, of which, dinucleotide repeat was the most abundant (56.80%), followed by mononucleotide repeat (30.23%). Furthermore, 60 pairs of primers were designed and synthesized based on microsatellite sequences, of which 15 were polymorphic in a wild population. A total of 91 alleles were found, with an average of 6.07 per locus. Number of alleles, observed and expected heterozygosity per locus ranged from two to 13, from 0.250 to 0.862, and from 0.396 to 0.901, respectively. Twelve loci were highly informative (PIC > 0.5), and the others were medium informative (0.25 disequilibrium was detected between loci pairs. This study provided a large number of genomic resources and 15 polymorphic microsatellite loci that should be helpful for the further genetic studies in S. sihama.
    Matched MeSH terms: Linkage Disequilibrium/genetics
  4. Genetic association of SNPs in the FTO gene and predisposition to obesity in Malaysian Malays
    Apalasamy YD, Ming MF, Rampal S, Bulgiba A, Mohamed Z
    Braz. J. Med. Biol. Res., 2012 Dec;45(12):1119-26.
    PMID: 22911346
    The common variants in the fat mass- and obesity-associated (FTO) gene have been previously found to be associated with obesity in various adult populations. The objective of the present study was to investigate whether the single nucleotide polymorphisms (SNPs) and linkage disequilibrium (LD) blocks in various regions of the FTO gene are associated with predisposition to obesity in Malaysian Malays. Thirty-one FTO SNPs were genotyped in 587 (158 obese and 429 non-obese) Malaysian Malay subjects. Obesity traits and lipid profiles were measured and single-marker association testing, LD testing, and haplotype association analysis were performed. LD analysis of the FTO SNPs revealed the presence of 57 regions with complete LD (D' = 1.0). In addition, we detected the association of rs17817288 with low-density lipoprotein cholesterol. The FTO gene may therefore be involved in lipid metabolism in Malaysian Malays. Two haplotype blocks were present in this region of the FTO gene, but no particular haplotype was found to be significantly associated with an increased risk of obesity in Malaysian Malays.
    Matched MeSH terms: Linkage Disequilibrium/genetics*
  5. Intragenic linkage disequilibrium structure of the human perilipin gene (PLIN) and haplotype association with increased obesity risk in a multiethnic Asian population
    Qi L, Tai ES, Tan CE, Shen H, Chew SK, Greenberg AS, et al.
    J Mol Med (Berl), 2005 Jun;83(6):448-56.
    PMID: 15770500
    Perilipin is a lipid droplet surface protein present in adipocytes and steroidogenic cells. We examined five common single nucleotide polymorphisms (SNPs) at the perilipin (PLIN) locus (PLIN 6209C>T, 10171A>T, 11482G>A, 13041A>G, and 14995A>T) to investigate their association with obesity risk. The study population included 4,131 subjects of three ethnic groups (Chinese, Malay, and Indian) from Singapore. The prevalence of obesity in Malays and Indians was much higher than in Chinese. Moreover, in these groups the prevalence of obesity was three times higher in women than in men. Crude analysis indicated that haplotype 11212 (CAAAT) is shared by Malays and Indians and is significantly associated with increased obesity risk as compared to the most common haplotype 21111 (TAGAA): OR 1.65 (95% CI 1.11-2.46) in Malays and 1.94 (95% CI 1.06-3.53) in Indians. No associations between PLIN haplotypes and obesity risk were found in Chinese. To simplify the haplotype analyses we used a subgroup of three SNPs (11482G>A, 13041A>G, and 14995A>T) in positive linkage disequilibrium. These analyses revealed similar associations, showing that haplotypes XX212 (XXAAT) and XX222 (XXAGT) are associated with increased obesity risk in Malays OR 2.04 (95% CI 1.28-3.25) and 2.05 (95% CI 1.35-3.12) respectively, and that haplotype XXX212 (XXAAT) is significantly associated with increased obesity risk in Indians OR 2.16 (95% CI 1.10-4.26) after adjusting for covariates including age, sex, smoking, alcohol consumption, exercise, and diabetes status. Moreover, individual SNP analyses demonstrated that the PLIN 14995A>T SNP is the most informative single genetic marker for the observed haplotype association, being significantly associated with increased obesity risk in both Malays OR 2.28 (95% CI 1.45-3.57) and Indians OR 2.04 (95% CI 1.08-3.64). These results support the role of the PLIN locus as an ethnically dependent modulator of obesity risk in humans.
    Matched MeSH terms: Linkage Disequilibrium/genetics*
  6. Contribution of GABRG2 Polymorphisms to Risk of Epilepsy and Febrile Seizure: a Multicenter Cohort Study and Meta-analysis
    Haerian BS, Baum L, Kwan P, Cherny SS, Shin JG, Kim SE, et al.
    Mol Neurobiol, 2016 10;53(8):5457-67.
    PMID: 26452361 DOI: 10.1007/s12035-015-9457-y
    Gamma-aminobutyric acid receptor (GABA-A) is the most common receptor of fast synaptic inhibition in the human brain. Gamma protein encoded by the GABRG2 gene is one of the subunits of the GABA-A receptor, which plays an essential role in the function of this receptor. Several studies have identified various febrile seizure (FS) and epilepsy risk variants of GABRG2 gene in different populations, but some others did not support these results. The aim of this case-control study is to investigate whether GABRG2 polymorphisms contribute to susceptibility for FS and epilepsy in pooled data of three cohorts, from Malaysia (composed of Malay, Chinese, and Indian), Hong Kong, and Korea. Furthermore, the pooled dataset of these cohorts with previous reports were meta-analyzed for determining the risk effect size of the rs211037 polymorphism on FS and symptomatic epilepsy (SE). The rs211037, rs210987, rs440218, rs2422106, rs211014, and rs401750 polymorphisms were genotyped in the 6442 subjects (1729 epilepsy and 4713 controls). Results of the case-control study showed associations between rs211037 and the risk of SE in the pooled data from all cohorts (T vs. C, p = 3 × 10(-5), and TT vs. CC, p = 2 × 10(-5)) and the risk of partial seizure in the combined data of Malaysia and Hong Kong (both T vs. C and TT vs. CC, p = 2 × 10(-6)). The rs211037-rs210987 and rs2422106-rs211014-rs401750 haplotypes were also associated with susceptibility to SE in Chinese. Meta-analysis of all Asians identified association between rs211037 and FS and SE (T vs. C, p = 4 × 10(-4), and p = 4 × 10(-3), respectively). In conclusion, rs211037 alone may be a risk factor for FS, partial seizure, and SE, and in linkage disequilibrium with rs210987 can contribute to FS and SE in Asians, particularly in Chinese.
    Matched MeSH terms: Linkage Disequilibrium/genetics
  7. De novo assembly of genome and development of polymorphic microsatellite loci in the blue swimming crab (Portunus pelagicus) using RAD approach
    Wu Q, Miao G, Li X, Liu W, Ikhwanuddin M, Ma H
    Mol Biol Rep, 2018 Dec;45(6):1913-1918.
    PMID: 30203240 DOI: 10.1007/s11033-018-4339-9
    The blue swimming crab (Portunus pelagicus) is a valuable marine fishery resource in Indo-West Pacific Ocean. So far, rare genetic resource of this species is available. In this report, the restriction-site associated DNA (RAD) approach was employed to mine the genomic information and identify molecular markers in P. pelagicus. A total of 0.82 Gbp clean data were generated from the genome of individual "X2A". De novo assembly produced 85,796 contigs with an average length of 339 bp. A total of 45,464 putative SNPs and 17,983 microsatellite loci were identified from the genomes of ten individuals. Furthermore, 31 pairs of primers were successfully designed, with 16 of them exhibiting polymorphism in a wild population. For these polymorphic loci, the expected and observed alleles per locus ranged from 1.064 to 7.314 and from 2 to 11, respectively. The expected and observed heterozygosity per locus ranged from 0.0615 to 0.819 and from 0.0626 to 1.000, respectively. Nine loci showed high informative with polymorphism information content (PIC) > 0.5. Five loci significantly deviated from Hardy-Weinberg equilibrium in the samples analyzed. No linkage disequilibrium was found among the 16 polymorphic microsatellite loci. This study provided massive genetic resource and polymorphic molecular markers that should be helpful for studies on conservation genetics, population dynamics and genetic diversity of P. pelagicus and related crab species.
    Matched MeSH terms: Linkage Disequilibrium/genetics
  8. Fulltext Genetic Diversity of Plasmodium falciparum Populations in Malaria Declining Areas of Sabah, East Malaysia
    Mohd Abd Razak MR, Sastu UR, Norahmad NA, Abdul-Karim A, Muhammad A, Muniandy PK, et al.
    PLoS One, 2016;11(3):e0152415.
    PMID: 27023787 DOI: 10.1371/journal.pone.0152415
    Malaysia has a national goal to eliminate malaria by 2020. Understanding the genetic diversity of malaria parasites in residual transmission foci can provide invaluable information which may inform the intervention strategies used to reach elimination targets. This study was conducted to determine the genetic diversity level of P. falciparum isolates in malaria residual foci areas of Sabah. Malaria active case detection was conducted in Kalabakan and Kota Marudu. All individuals in the study sites were screened for malaria infection by rapid diagnostic test. Blood from P. falciparum-infected individuals were collected on filter paper prior to DNA extraction. Genotyping was performed using merozoite surface protein-1 (MSP-1), merozoite surface protein-2 (MSP-2), glutamate rich protein (GLURP) and 10 neutral microsatellite loci markers. The size of alleles, multiplicity of infection (MOI), mean number of alleles (Na), expected heterozygosity (He), linkage disequilibrium (LD) and genetic differentiation (FST) were determined. In Kalabakan, the MSP-1 and MSP-2 alleles were predominantly K1 and FC27 family types, respectively. The GLURP genotype VI (751-800 bp) was predominant. The MOI for MSP-1 and MSP-2 were 1.65 and 1.20, respectively. The Na per microsatellite locus was 1.70. The He values for MSP-1, MSP-2, GLURP and neutral microsatellites were 0.17, 0.37, 0.70 and 0.33, respectively. In Kota Marudu, the MSP-1 and MSP-2 alleles were predominantly MAD20 and 3D7 family types, respectively. The GLURP genotype IV (651-700 bp) was predominant. The MOI for both MSP-1 and MSP-2 was 1.05. The Na per microsatellite locus was 3.60. The He values for MSP-1, MSP-2, GLURP and neutral microsatellites were 0.24, 0.25, 0.69 and 0.30, respectively. A significant LD was observed in Kalabakan (0.495, p<0.01) and Kota Marudu P. falciparum populations (0.601, p<0.01). High genetic differentiation between Kalabakan and Kota Marudu P. falciparum populations was observed (FST = 0.532). The genetic data from the present study highlighted the limited diversity and contrasting genetic pattern of P. falciparum populations in the malaria declining areas of Sabah.
    Matched MeSH terms: Linkage Disequilibrium/genetics
  9. Gender-specific association of NFKBIA promoter polymorphisms with the risk of sporadic colorectal cancer
    Tan SC, Suzairi MS, Aizat AA, Aminudin MM, Nurfatimah MS, Bhavaraju VM, et al.
    Med Oncol, 2013 Dec;30(4):693.
    PMID: 23996241 DOI: 10.1007/s12032-013-0693-6
    The inhibitory protein IκBα, encoded by the NFKBIA gene, plays an important role in regulating the activity of nuclear factor-kappa B, a transcription factor which has been implicated in the initiation and progression of cancers. This study aimed to evaluate the association of NFKBIA -826C>T (rs2233406) and -881A>G (rs3138053) polymorphisms with the risk of sporadic colorectal cancer (CRC) in Malaysian population. A case-control study comprising 474 subjects (237 CRC patients and 237 cancer-free controls) was carried out. The polymorphisms were genotyped from the genomic DNA of the study subjects employing PCR-RFLP, followed by DNA sequencing. The association between the polymorphic genotypes and CRC risk was evaluated by deriving odds ratios (ORs) and 95 % confidence intervals (CIs) using unconditional logistic regression analysis. The two polymorphisms were in complete and perfect linkage disequilibrium (D' = 1.0, r (2) = 1.0). Overall, no statistically significant CRC risk association was found for the polymorphisms (P > 0.05). A similar lack of association was observed when the data were stratified according to ethnicity (P > 0.05). However, stratification by gender revealed a significant inverse association between the heterozygous genotype of the polymorphisms and the risk of CRC among females (OR 0.53, 95 % CI 0.29-0.97, P = 0.04), but not among males (P > 0.05). In conclusion, the heterozygous genotype of the polymorphisms could contribute to a significantly decreased CRC risk among females, but not males, in the Malaysian population.
    Matched MeSH terms: Linkage Disequilibrium/genetics
  10. Fulltext Selected neuropeptide genes show genetic differentiation between Africans and non-Africans
    Tai KY, Wong K, Aghakhanian F, Parhar IS, Dhaliwal J, Ayub Q
    BMC Genet, 2020 03 14;21(1):31.
    PMID: 32171244 DOI: 10.1186/s12863-020-0835-8
    BACKGROUND: Publicly available genome data provides valuable information on the genetic variation patterns across different modern human populations. Neuropeptide genes are crucial to the nervous, immune, endocrine system, and physiological homeostasis as they play an essential role in communicating information in neuronal functions. It remains unclear how evolutionary forces, such as natural selection and random genetic drift, have affected neuropeptide genes among human populations. To date, there are over 100 known human neuropeptides from the over 1000 predicted peptides encoded in the genome. The purpose of this study is to analyze and explore the genetic variation in continental human populations across all known neuropeptide genes by examining highly differentiated SNPs between African and non-African populations.

    RESULTS: We identified a total of 644,225 SNPs in 131 neuropeptide genes in 6 worldwide population groups from a public database. Of these, 5163 SNPs that had ΔDAF |(African - non-African)| ≥ 0.20 were identified and fully annotated. A total of 20 outlier SNPs that included 19 missense SNPs with a moderate impact and one stop lost SNP with high impact, were identified in 16 neuropeptide genes. Our results indicate that an overall strong population differentiation was observed in the non-African populations that had a higher derived allele frequency for 15/20 of those SNPs. Highly differentiated SNPs in four genes were particularly striking: NPPA (rs5065) with high impact stop lost variant; CHGB (rs6085324, rs236150, rs236152, rs742710 and rs742711) with multiple moderate impact missense variants; IGF2 (rs10770125) and INS (rs3842753) with moderate impact missense variants that are in linkage disequilibrium. Phenotype and disease associations of these differentiated SNPs indicated their association with hypertension and diabetes and highlighted the pleiotropic effects of these neuropeptides and their role in maintaining physiological homeostasis in humans.

    CONCLUSIONS: We compiled a list of 131 human neuropeptide genes from multiple databases and literature survey. We detect significant population differentiation in the derived allele frequencies of variants in several neuropeptide genes in African and non-African populations. The results highlights SNPs in these genes that may also contribute to population disparities in prevalence of diseases such as hypertension and diabetes.

    Matched MeSH terms: Linkage Disequilibrium/genetics
  11. A genome-wide association study identifies ITGA9 conferring risk of nasopharyngeal carcinoma
    Ng CC, Yew PY, Puah SM, Krishnan G, Yap LF, Teo SH, et al.
    J Hum Genet, 2009 Jul;54(7):392-7.
    PMID: 19478819 DOI: 10.1038/jhg.2009.49
    To identify a gene(s) susceptible to nasopharyngeal carcinoma (NPC), we carried out a genome-wide association study (GWAS) through genotyping of more than 500,000 tag single-nucleotide polymorphisms (SNPs), using an initial sample set of 111 unrelated NPC patients and 260 controls of a Malaysian Chinese population. We further evaluated the top 200 SNPs showing the smallest P-values, using a replication sample set that consisted of 168 cases and 252 controls. The combined analysis of the two sets of samples found an SNP in intron 3 of the ITGA9 (integrin-alpha 9) gene, rs2212020, to be strongly associated with NPC (P=8.27 x 10(-7), odds ratio (OR)=2.24, 95% confidence intervals (CI)=1.59-3.15). The gene is located at 3p21 which is commonly deleted in NPC cells. We subsequently genotyped additional 19 tag SNPs within a 40-kb linkage disequilibrium (LD) block surrounding this landmark SNP. Among them, SNP rs189897 showed the strongest association with a P-value of 6.85 x 10(-8) (OR=3.18, 95% CI=1.94-5.21), suggesting that a genetic variation(s) in ITGA9 may influence susceptibility to NPC in the Malaysian Chinese population.
    Matched MeSH terms: Linkage Disequilibrium/genetics
  12. Fulltext Haplotype CGC from XPD, hOGG1 and ITGA2 polymorphisms increases the risk of nasopharyngeal carcinoma in Malaysia
    Ban EZ, Lye MS, Chong PP, Yap YY, Lim SYC, Abdul Rahman H
    PLoS One, 2017;12(11):e0187200.
    PMID: 29121049 DOI: 10.1371/journal.pone.0187200
    BACKGROUND: 8-oxoG, a common DNA lesion resulting from reactive oxygen species (ROS), has been shown to be associated with cancer initiation. hOGG1 DNA glycosylase is the primary enzyme responsible for excision of 8-oxoG through base excision repair (BER). Integrins are members of a family of cell surface receptors that mediate the cell-cell and extracellular matrix (ECM) interactions. Integrins are involved in almost every aspect of carcinogenesis, from cell differentiation, cell proliferation, metastasis to angiogenesis. Loss of ITGA2 expression was associated with enhanced tumor intravasation and metastasis of breast and colon cancer. XPD gene encodes DNA helicase enzyme that is involved in nucleotide excision repair (NER). It is shown in previous research that XPD homozygous wildtype Lys/Lys genotype was associated with higher odds of NPC.

    METHODS: We conducted a 1 to N case-control study involving 300 nasopharyngeal carcinoma (NPC) cases and 533 controls matched by age, gender and ethnicity to investigate the effect of hOGG1 Ser326Cys, ITGA2 C807T and XPD Lys751Gln polymorphisms on NPC risk. Linkage disequilibrium and haplotype analysis were conducted to explore the association of allele combinations with NPC risk. Restriction fragment length polymorphism (RFLP-PCR) was used for DNA genotyping.

    RESULTS: No significant association was observed between hOGG1 Ser326Cys and ITGA2 C807T polymorphisms with NPC risk after adjustment for age, gender, ethnicity, cigarette smoking, alcohol and salted fish consumption. Lys/Lys genotype of XPD Lys751Gln polymorphism was associated with increased NPC risk (OR = 1.60, 95% CI = 1.06-2.43). Subjects with history of smoking (OR = 1.81, 95% CI = 1.26-2.60), and salted fish consumption before age of 10 (OR = 1.77, 95% CI = 1.30-2.42) were observed to have increased odds of NPC. The odds of developing NPC of CGC haplotype was significantly higher compared to reference AGC haplotype (OR = 2.20, 95% CI = 1.06-4.58).

    CONCLUSION: The allele combination of CGC from hOGG1, ITGA2 and XPD polymorphisms was significantly associated with increased odds of NPC.

    Matched MeSH terms: Linkage Disequilibrium/genetics
  13. ABCA1 gene polymorphisms and their associations with coronary artery disease and plasma lipids in males from three ethnic populations in Singapore
    Tan JH, Low PS, Tan YS, Tong MC, Saha N, Yang H, et al.
    Hum Genet, 2003 Jul;113(2):106-17.
    PMID: 12709788
    Mutations in the ATP-binding cassette transporter ABCA1 underlie Tangier disease and familial hypoalphaliproteinemia (FHA), disorders that are characterised by reduced high-density lipoprotein-cholesterol (HDL-C) concentration and cholesterol efflux, and increased coronary artery disease (CAD). We explored if polymorphisms in the ABCA1 gene are associated with CAD and variations in plasma lipid levels, especially HDL-C, and whether the associations may depend on ethnicity. Male cases and controls from the Singapore Chinese, Malay and Indian populations were genotyped for five ABCA1 single nucleotide polymorphisms. Various single-locus frequency distribution differences between cases and controls were detected in different ethnic groups: the promoter -14C>T in Indians, exon 18 M883I in Malays, and 3'-untranslated (UTR) region 8994A>G in Chinese. For the Malay population, certain haplotypes carrying the I825- A (exon 17) and M883- G alleles were more frequent among cases than controls, whereas the converse was true for the alternative configuration of V825- G and I883- A, and this association was reinforced in multi-locus disequilibrium analysis that utilized genotypic data. In the healthy controls, associations were found for -14C>T genotypes with HDL-C in Chinese; 237indelG (5'UTR) with apolipoprotein A1 (apoA1) in Malays and total cholesterol (TC) in Indians; M883I with lipoprotein(a) [Lp(a)] in Malays and apolipoprotein B (apoB) in Chinese; and 8994A>G with Lp(a) in Malays, and TC, low-density lipoprotein-cholesterol (LDL-C) as well as apoB in Indians. While genotype-phenotype associations were not reproduced across populations and loci, V825I and M883I were clearly associated with CAD status in Malays with no effects on HDL-C or apoA1.
    Matched MeSH terms: Linkage Disequilibrium/genetics
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