Acute liver failure is a severe, but rare, outcome of hepatitis A virus infection. Unusual presen... more Acute liver failure is a severe, but rare, outcome of hepatitis A virus infection. Unusual presentations of prevalent infections have often been attributed to pathogen-specific immune deficits that exhibit Mendelian inheritance. Genome-wide resequencing of unrelated cases has proven to be a powerful approach for identifying highly penetrant risk alleles that underlie such syndromes. Rare mutations likely to affect protein expression or function can be identified from sequence data, and their association with a similarly rare phenotype rests on their existence in multiple affected individuals. A rare or novel sequence variant that is enriched to a significant degree in a genetically diverse cohort suggests a candidate susceptibility allele. Whole genome sequencing of ten individuals from ethnically diverse backgrounds with HAV-associated acute liver failure was performed. A set of rational filtering criteria was used to identify genetic variants that are rare in the population, but enriched in this cohort. Single nucleotide polymorphisms, insertions, and deletions were considered and autosomal dominant, autosomal recessive, and polygenic models were applied. Analysis of the protein-coding exome identified no single gene with putatively deleterious mutations shared by multiple individuals, arguing against a simple Mendelian model of inheritance. A number of rare variants were significantly enriched in this cohort, consistent with a complex and genetically heterogeneous trait. Several of the variants identified in this genome-wide study lie within genes important to hepatic pathophysiology and are candidate susceptibility alleles for hepatitis A virus infection.
This study analyzes the autosomal short tandem repeats (STRs) variation and the presence of Y chr... more This study analyzes the autosomal short tandem repeats (STRs) variation and the presence of Y chromosomal haplogroups from 44 individuals of the Kayah or Red Karen (KA) in Northern Thailand. The results based on autosomal STRs indicated that the KA exhibited closer genetic relatedness to populations from adjacent regions in Southeast Asia (SEA) than populations from Northeast Asia (NEA) and Tibet. Moreover, an admixed origin of the KA forming three population groups was observed: NEA, Southern China, and Northern Thailand. The NEA populations made a minor genetic contribution to the KA, while the rest came from populations speaking Sino-Tibetan (ST) languages from Southern China and Tai-Kadai (TK) speaking groups from Northern Thailand. The presence of six paternal haplogroups, composed of dual haplogroups prevalent in NEA (NO, N, and D1) and SEA (O2 and O3) as well as the intermediate genetic position of the KA between the SEA and NEA also indicated an admixed origin of male KA lineages. Our genetic results thus agree with findings in linguistics that Karenic languages are ST languages that became heavily influenced by TK during their southward spread. A result of the Mongol invasions during the 13(th) century A.D. is one possible explanation for genetic contribution of NEA to the KA.
Familial aggregation of Chagas cardiac disease in T. cruzi-infected persons suggests that human g... more Familial aggregation of Chagas cardiac disease in T. cruzi-infected persons suggests that human genetic variation may be an important determinant of disease progression. To perform a GWAS using a well-characterized cohort to detect single nucleotide polymorphisms (SNPs) and genes associated with cardiac outcomes. A retrospective cohort study was developed by the NHLBI REDS-II program in Brazil. Samples were collected from 499 T. cruzi seropositive blood donors who had donated between 1996 and 2002, and 101 patients with clinically diagnosed Chagas cardiomyopathy. In 2008-2010, all subjects underwent a complete medical examination. After genotype calling, quality control filtering with exclusion of 20 cases, and imputation of 1,000 genomes variants; association analysis was performed for 7 cardiac and parasite related traits, adjusting for population stratification. The cohort showed a wide range of African, European, and modest Native American admixture proportions, consistent with ...
ABSTRACT The genetic structure and diversity of the Khon Mueang, who constitute the majority of t... more ABSTRACT The genetic structure and diversity of the Khon Mueang, who constitute the majority of the current northern Thai populations, is poorly understood. In present study, 433 unrelated individuals from 10 Khon Mueang villages, located in different geographic areas along historical Yuan migration route, were analyzed using the mtDNA hypervariable region (HVR) 1 and 17 Y chromosome short tandem repeats (Y-STRs) as markers. The studied populations from the Chiang Mai-Lamphun basin showed the evidence of demographic expansion and gene flow process in this area. Genetic structure of the geographically diverse Khon Mueang was driven by geography, while genetic differentiation of Chiang Mai-Lamphun populations was shaped by genetic exchange with the neighbouring populations in the area. Contrasting patterns of mtDNA and Y chromosome variations, influenced by sex-bias rates of migration and admixture, suggests that male and female Khon Mueang do not have identical demographic histories.
... POPULATIONS IN THAILAND METAWEE SRIKUMMOOL Department of Biology, Chiang Mai University DAORO... more ... POPULATIONS IN THAILAND METAWEE SRIKUMMOOL Department of Biology, Chiang Mai University DAOROONG KANGWANPONG Department of Biology, Chiang Mai University NADIA SINGH Program for ... La Sage, September 6-9. Parsons, TJ and Irwin, JA 2000. ...
Four single nucleotide polymorphisms (SNPs) and a variable number of tandem repeats (VNTR) polymo... more Four single nucleotide polymorphisms (SNPs) and a variable number of tandem repeats (VNTR) polymorphism located within disease associated/causing genes were typed in four populations of different tribal and ethnic affiliation from the Sudan. The genotype and allele frequencies were compared with those of other groups from published and unpublished data of world populations. The combined Sudanese sample conformed with Hardy-Weinberg equilibrium (HWE) expectation. However, population sub-structuring according to ethnic/linguistic group indicated at least two SNPs in departure from HWE. Differences in allele frequencies and genotype distribution between groups was also noted in three of the four SNPs. The other loci were distributed homogeneously within the populations studied with genotype frequencies in agreement with HWE expectation. These results highlight the importance of inter-population stratification for polymorphic markers, as well as the potential influence of evolutionary h...
Tumor necrosis factor alpha-inducible protein 3 (TNFAIP3) encodes a ubiquitin-modifying protein, ... more Tumor necrosis factor alpha-inducible protein 3 (TNFAIP3) encodes a ubiquitin-modifying protein, A20, that is a critical regulator of inflammatory responses. TNFAIP3 polymorphisms are associated with the susceptibility to multiple autoimmune diseases (AIDs) including psoriasis, systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis and celiac disease. In order to refine the TNFAIP3 association signal in psoriasis and identify candidate causal variants, we performed imputation and meta-analysis of the TNFAIP3 region in five European ancestry cohorts totaling 4704 psoriasis cases and 7805 controls. We identified 49 variants whose significance exceeded a corrected Bonferroni threshold, with the top variant being rs582757 (P=6.07 × 10(-12), odds ratio (OR)=1.23). Conditional analysis revealed a suggestive independent association at rs6918329 (Pcond=7.22 × 10(-5), OR=1.15). Functional annotation of the top variants identified several with a strong evidence of regulatory p...
Recent genome-wide association studies (GWAS) have identified 38 obesity-associated loci among Eu... more Recent genome-wide association studies (GWAS) have identified 38 obesity-associated loci among European populations. However, their contribution to obesity in other ethnicities is largely unknown. We utilised five GWAS (N=10 482) from Chinese (three cohorts, including one with type 2 diabetes and another one of children), Malay and Indian ethnic groups from Singapore. Data sets were analysed individually and subsequently in combined meta-analysis for Z-score body-mass index (BMI) associations. Variants at the FTO locus showed the strongest associations with BMI Z-score after meta-analysis (P-values 1.16 × 10(-7)-7.95 × 10(-7)). We further detected associations with nine other index obesity variants close to the MC4R, GNPDA2, TMEM18, QPCTL/GIPR, BDNF, ETV5, MAP2K5/SKOR1, SEC16B and TNKS/MSRA loci (meta-analysis P-values ranging from 3.58 × 10(-4)-1.44 × 10(-2)). Three other single-nucleotide polymorphisms (SNPs) from CADM2, PTBP2 and FAIM2 were associated with BMI (P-value ≤ 0.0418) ...
Annals of the Academy of Medicine, Singapore, 2004
Twin studies are a most effective method to analyse gene and environment interactions. Using data... more Twin studies are a most effective method to analyse gene and environment interactions. Using data from the Singapore National Registry of Births and Deaths (SNRBD), this paper describes the number of twin and multiple births among different ethnic populations in Singapore. All births recorded in the SNRBD from 1 January 1986 to 31 December 2001 were analysed. Outcomes measured were twin and triple birth rates (per 1000 maternities) of the 3 main ethnic groups in Singapore (Chinese, Malays and Asian Indians). Further outcomes were calculated using Weinberg's differential rule to estimate the number of monozygotic and dizygotic twins. Overall twin birth rates have steadily increased across all ethnic groups (7 to 9/1000). The largest increase in multiple births among the ethnic groups were twins born to Asian Indian fathers (6.9 to 9.9/1000) and Malay mothers (5.9 to 9.8/1000). A significant difference in birth rates between the ethnic groups was found during the years 1994 to 199...
Acute liver failure is a severe, but rare, outcome of hepatitis A virus infection. Unusual presen... more Acute liver failure is a severe, but rare, outcome of hepatitis A virus infection. Unusual presentations of prevalent infections have often been attributed to pathogen-specific immune deficits that exhibit Mendelian inheritance. Genome-wide resequencing of unrelated cases has proven to be a powerful approach for identifying highly penetrant risk alleles that underlie such syndromes. Rare mutations likely to affect protein expression or function can be identified from sequence data, and their association with a similarly rare phenotype rests on their existence in multiple affected individuals. A rare or novel sequence variant that is enriched to a significant degree in a genetically diverse cohort suggests a candidate susceptibility allele. Whole genome sequencing of ten individuals from ethnically diverse backgrounds with HAV-associated acute liver failure was performed. A set of rational filtering criteria was used to identify genetic variants that are rare in the population, but enriched in this cohort. Single nucleotide polymorphisms, insertions, and deletions were considered and autosomal dominant, autosomal recessive, and polygenic models were applied. Analysis of the protein-coding exome identified no single gene with putatively deleterious mutations shared by multiple individuals, arguing against a simple Mendelian model of inheritance. A number of rare variants were significantly enriched in this cohort, consistent with a complex and genetically heterogeneous trait. Several of the variants identified in this genome-wide study lie within genes important to hepatic pathophysiology and are candidate susceptibility alleles for hepatitis A virus infection.
This study analyzes the autosomal short tandem repeats (STRs) variation and the presence of Y chr... more This study analyzes the autosomal short tandem repeats (STRs) variation and the presence of Y chromosomal haplogroups from 44 individuals of the Kayah or Red Karen (KA) in Northern Thailand. The results based on autosomal STRs indicated that the KA exhibited closer genetic relatedness to populations from adjacent regions in Southeast Asia (SEA) than populations from Northeast Asia (NEA) and Tibet. Moreover, an admixed origin of the KA forming three population groups was observed: NEA, Southern China, and Northern Thailand. The NEA populations made a minor genetic contribution to the KA, while the rest came from populations speaking Sino-Tibetan (ST) languages from Southern China and Tai-Kadai (TK) speaking groups from Northern Thailand. The presence of six paternal haplogroups, composed of dual haplogroups prevalent in NEA (NO, N, and D1) and SEA (O2 and O3) as well as the intermediate genetic position of the KA between the SEA and NEA also indicated an admixed origin of male KA lineages. Our genetic results thus agree with findings in linguistics that Karenic languages are ST languages that became heavily influenced by TK during their southward spread. A result of the Mongol invasions during the 13(th) century A.D. is one possible explanation for genetic contribution of NEA to the KA.
Familial aggregation of Chagas cardiac disease in T. cruzi-infected persons suggests that human g... more Familial aggregation of Chagas cardiac disease in T. cruzi-infected persons suggests that human genetic variation may be an important determinant of disease progression. To perform a GWAS using a well-characterized cohort to detect single nucleotide polymorphisms (SNPs) and genes associated with cardiac outcomes. A retrospective cohort study was developed by the NHLBI REDS-II program in Brazil. Samples were collected from 499 T. cruzi seropositive blood donors who had donated between 1996 and 2002, and 101 patients with clinically diagnosed Chagas cardiomyopathy. In 2008-2010, all subjects underwent a complete medical examination. After genotype calling, quality control filtering with exclusion of 20 cases, and imputation of 1,000 genomes variants; association analysis was performed for 7 cardiac and parasite related traits, adjusting for population stratification. The cohort showed a wide range of African, European, and modest Native American admixture proportions, consistent with ...
ABSTRACT The genetic structure and diversity of the Khon Mueang, who constitute the majority of t... more ABSTRACT The genetic structure and diversity of the Khon Mueang, who constitute the majority of the current northern Thai populations, is poorly understood. In present study, 433 unrelated individuals from 10 Khon Mueang villages, located in different geographic areas along historical Yuan migration route, were analyzed using the mtDNA hypervariable region (HVR) 1 and 17 Y chromosome short tandem repeats (Y-STRs) as markers. The studied populations from the Chiang Mai-Lamphun basin showed the evidence of demographic expansion and gene flow process in this area. Genetic structure of the geographically diverse Khon Mueang was driven by geography, while genetic differentiation of Chiang Mai-Lamphun populations was shaped by genetic exchange with the neighbouring populations in the area. Contrasting patterns of mtDNA and Y chromosome variations, influenced by sex-bias rates of migration and admixture, suggests that male and female Khon Mueang do not have identical demographic histories.
... POPULATIONS IN THAILAND METAWEE SRIKUMMOOL Department of Biology, Chiang Mai University DAORO... more ... POPULATIONS IN THAILAND METAWEE SRIKUMMOOL Department of Biology, Chiang Mai University DAOROONG KANGWANPONG Department of Biology, Chiang Mai University NADIA SINGH Program for ... La Sage, September 6-9. Parsons, TJ and Irwin, JA 2000. ...
Four single nucleotide polymorphisms (SNPs) and a variable number of tandem repeats (VNTR) polymo... more Four single nucleotide polymorphisms (SNPs) and a variable number of tandem repeats (VNTR) polymorphism located within disease associated/causing genes were typed in four populations of different tribal and ethnic affiliation from the Sudan. The genotype and allele frequencies were compared with those of other groups from published and unpublished data of world populations. The combined Sudanese sample conformed with Hardy-Weinberg equilibrium (HWE) expectation. However, population sub-structuring according to ethnic/linguistic group indicated at least two SNPs in departure from HWE. Differences in allele frequencies and genotype distribution between groups was also noted in three of the four SNPs. The other loci were distributed homogeneously within the populations studied with genotype frequencies in agreement with HWE expectation. These results highlight the importance of inter-population stratification for polymorphic markers, as well as the potential influence of evolutionary h...
Tumor necrosis factor alpha-inducible protein 3 (TNFAIP3) encodes a ubiquitin-modifying protein, ... more Tumor necrosis factor alpha-inducible protein 3 (TNFAIP3) encodes a ubiquitin-modifying protein, A20, that is a critical regulator of inflammatory responses. TNFAIP3 polymorphisms are associated with the susceptibility to multiple autoimmune diseases (AIDs) including psoriasis, systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis and celiac disease. In order to refine the TNFAIP3 association signal in psoriasis and identify candidate causal variants, we performed imputation and meta-analysis of the TNFAIP3 region in five European ancestry cohorts totaling 4704 psoriasis cases and 7805 controls. We identified 49 variants whose significance exceeded a corrected Bonferroni threshold, with the top variant being rs582757 (P=6.07 × 10(-12), odds ratio (OR)=1.23). Conditional analysis revealed a suggestive independent association at rs6918329 (Pcond=7.22 × 10(-5), OR=1.15). Functional annotation of the top variants identified several with a strong evidence of regulatory p...
Recent genome-wide association studies (GWAS) have identified 38 obesity-associated loci among Eu... more Recent genome-wide association studies (GWAS) have identified 38 obesity-associated loci among European populations. However, their contribution to obesity in other ethnicities is largely unknown. We utilised five GWAS (N=10 482) from Chinese (three cohorts, including one with type 2 diabetes and another one of children), Malay and Indian ethnic groups from Singapore. Data sets were analysed individually and subsequently in combined meta-analysis for Z-score body-mass index (BMI) associations. Variants at the FTO locus showed the strongest associations with BMI Z-score after meta-analysis (P-values 1.16 × 10(-7)-7.95 × 10(-7)). We further detected associations with nine other index obesity variants close to the MC4R, GNPDA2, TMEM18, QPCTL/GIPR, BDNF, ETV5, MAP2K5/SKOR1, SEC16B and TNKS/MSRA loci (meta-analysis P-values ranging from 3.58 × 10(-4)-1.44 × 10(-2)). Three other single-nucleotide polymorphisms (SNPs) from CADM2, PTBP2 and FAIM2 were associated with BMI (P-value ≤ 0.0418) ...
Annals of the Academy of Medicine, Singapore, 2004
Twin studies are a most effective method to analyse gene and environment interactions. Using data... more Twin studies are a most effective method to analyse gene and environment interactions. Using data from the Singapore National Registry of Births and Deaths (SNRBD), this paper describes the number of twin and multiple births among different ethnic populations in Singapore. All births recorded in the SNRBD from 1 January 1986 to 31 December 2001 were analysed. Outcomes measured were twin and triple birth rates (per 1000 maternities) of the 3 main ethnic groups in Singapore (Chinese, Malays and Asian Indians). Further outcomes were calculated using Weinberg's differential rule to estimate the number of monozygotic and dizygotic twins. Overall twin birth rates have steadily increased across all ethnic groups (7 to 9/1000). The largest increase in multiple births among the ethnic groups were twins born to Asian Indian fathers (6.9 to 9.9/1000) and Malay mothers (5.9 to 9.8/1000). A significant difference in birth rates between the ethnic groups was found during the years 1994 to 199...
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