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1.  Molecular analysis of common polymorphisms within the human Tyrosinase locus and genetic association with pigmentation traits 
Pigment cell & melanoma research  2014;27(4):552-564.
We have compared the melanogenic activities of cultured melanocytes carrying two common TYR alleles as homozygous 192S-402R wildtype, heterozygous and homozygous variant. This includes assays of TYR protein, DOPAoxidase activity, glycosylation and temperature sensitivity of protein and DOPAoxidase levels. Homozygous wildtype strains on average had higher levels of TYR protein and enzyme activity than other genotypes. Homozygous 402Q/Q melanocytes produced significantly less TYR protein, displayed altered trafficking and glycosylation, with reduced DOPAoxidase. However, near wildtype TYR activity levels could be recovered at lower growth temperature. In a sample population from Southeast Queensland these two polymorphisms were present on four TYR haplotypes, designated as WT 192S-402R, 192Y-402R, 192S-402Q with a double variant 192Y-402Q of low frequency at 1.9%. Based on cell culture findings and haplotype associations, we have used an additive model to assess the penetrance of the ten possible TYR genotypes derived from the combination of these haplotypes.
PMCID: PMC4119297  PMID: 24739399
Tyrosinase; Pigmentation; Melanocyte; Albinism; Melanin
2.  Assessment of PALB2 as a Candidate Melanoma Susceptibility Gene 
PLoS ONE  2014;9(6):e100683.
Partner and localizer of BRCA2 (PALB2) interacts with BRCA2 to enable double strand break repair through homologous recombination. Similar to BRCA2, germline mutations in PALB2 have been shown to predispose to Fanconi anaemia as well as pancreatic and breast cancer. The PALB2/BRCA2 protein interaction, as well as the increased melanoma risk observed in families harbouring BRCA2 mutations, makes PALB2 a candidate for melanoma susceptibility. In order to assess PALB2 as a melanoma predisposition gene, we sequenced the entire protein-coding sequence of PALB2 in probands from 182 melanoma families lacking pathogenic mutations in known high penetrance melanoma susceptibility genes: CDKN2A, CDK4, and BAP1. In addition, we interrogated whole-genome and exome data from another 19 kindreds with a strong family history of melanoma for deleterious mutations in PALB2. Here we report a rare known deleterious PALB2 mutation (rs118203998) causing a premature truncation of the protein (p.Y1183X) in an individual who had developed four different cancer types, including melanoma. Three other family members affected with melanoma did not carry the variant. Overall our data do not support a case for PALB2 being associated with melanoma predisposition.
PMCID: PMC4065098  PMID: 24949998
3.  Polymorphisms in the Syntaxin 17 Gene are not Associated with Human Cutaneous Malignant Melanoma 
Melanoma research  2009;19(2):80-86.
The prevalence of cutaneous malignant melanoma (CMM) has increased significantly in most Caucasian populations in recent decades. Both genetic and environment are significant risk factors involved in the development of CMM. A germline mutation in the Syntaxin 17 (STX17) gene was recently identified in horses causing premature hair gray and associated with susceptibility to melanoma. We hypothesized that common germline variants in the STX17 gene might be associated with predisposition to human CMM or might interact with other melanoma risk genes. We conducted a case-control study by genotyping 26 tagging single nucleotide polymorphisms (SNPs) across the STX17 gene region in an Australian sample and performed logistic regression analysis for predicting the possible SNP interactions in a combined dataset. Our results do not support an association between CMM and any of the STX17 SNPs and provide no evidence for interactions between the melanoma risk SNP rs910873 on chromosome 20 and any of the STX17 SNPs. We conclude that common variants in the STX17 gene region do not play a key role in the pathogenesis of human melanoma.
PMCID: PMC3665505  PMID: 19209086
Syntaxin 17; melanoma; polymorphisms
5.  Evaluation of polymorphisms in predicted target sites for micro RNAs differentially expressed in endometriosis 
Molecular Human Reproduction  2010;17(2):92-103.
Previous microarray analyses identified 22 microRNAs (miRNAs) differentially expressed in paired ectopic and eutopic endometrium of women with and without endometriosis. To investigate further the role of these miRNAs in women with endometriosis, we conducted an association study aiming to explore the relationship between endometriosis risk and single-nucleotide polymorphisms (SNPs) in miRNA target sites for these differentially expressed miRNAs. A panel of 102 SNPs in the predicted miRNA binding sites were evaluated for an endometriosis association study and an ingenuity pathway analysis was performed. Fourteen rare variants were identified in this study. We found SNP rs14647 in the Wolf–Hirschhorn syndrome candidate gene1 (WHSC1) 3′UTR (untranslated region) was associated with endometriosis-related infertility presenting an odds ratio of 12.2 (95% confidence interval = 2.4–60.7, P = 9.03 × 10−5). SNP haplotype AGG in the solute carrier family 22, member 23 (SLC22A23) 3′UTR was associated with endometriosis-related infertility and more severe disease. With the individual genotyping data, ingenuity pathways analysis identified the tumour necrosis factor and cyclin-dependant kinase inhibitor as major factors in the molecular pathways. Significant associations between WHSC1 alleles and endometriosis-related infertility and SLC22A23 haplotypes and the disease severe stage were identified. These findings may help focus future research on subphenotypes of this disease. Replication studies in independent large sample sets to confirm and characterize the involvement of the gene variation in the pathogenesis of endometriosis are needed.
PMCID: PMC3023296  PMID: 20935158
miRNA; endometriosis; single-nucleotide polymorphism; haplotype
6.  Age-related susceptibility to severe malaria associated with galectin-2 in highland Papuans 
The Journal of infectious diseases  2010;202(1):117-124.
Age and host genetics are important determinants of malaria severity. Lymphotoxin-alpha (LTα) has been linked to the development of cerebral malaria (CM) and other severe malaria (SM) syndromes. Mutations in genes regulating LTα production contribute to other acute vascular diseases and may contribute to malaria pathogenesis.
We tested the association between rs7291467, a single nucleotide polymorphism (SNP) in the LTα-related gene encoding galectin-2 (LGALS2), disease severity and function in a case-control study of ethnic Highland Papuan adults and children with SM (n=380) and asymptomatic malaria-exposed controls (n=356), originating from a non-malaria-endemic region but residing in a lowland malaria-endemic area of Papua, Indonesia.
The LGALS2 SNP showed significant association with susceptibility to SM (including CM), in children (OR 2.02 [95% CI:1.14-3.57]) but not adults. In SM, the C-allele at rs7291467 was associated with enhanced galectin-2 transcript levels. In a separate group of Tanzanian children originating from a malaria-endemic region, we found preservation of the major ancestral LGALS2 allele and no association with susceptibility to CM.
Results suggest differences in the inflammatory contribution to the development of SM between children and adults in the same population, and potential differences between individuals originating from malaria-endemic and non-endemic areas.
PMCID: PMC2880661  PMID: 20500087
Malaria; Galectin-2; Inflammation; Gene regulation; Age; Severe Malaria; Cerebral Malaria
7.  Common Variation in the CYP17A1 and IFIT1 Genes on Chromosome 10 Does Not Contribute to the Risk of Endometriosis 
Endometriosis is a complex disease involving multiple susceptibility genes and environmental factors. Our previous studies on endometriosis identified a region of significant linkage on chromosome 10q. Two biological candidate genes (CYP17A1 and IFIT1) located on chromosome 10q, have previously been implicated in endometriosis and/or uterine function. We hypothesized that variation in CYP17A1 and/or IFIT1 could contribute to the risk of endometriosis and may account for some of the linkage signal on chromosome 10q. We genotyped 17 single nucleotide polymorphisms (SNPs) in the CYP17A1 and IFIT1 genes including SNP rs743572 previously associated with endometriosis in 768 endometriosis cases and 768 unrelated controls. We found no evidence for association between endometriosis and individual SNPs or SNP haplotypes in CYP17A1 and IFIT1. Common variation in these genes does not appear to be a major contributor to endometriosis susceptibility in our Australian sample.
PMCID: PMC2856969  PMID: 20411041
8.  Analysis of the 5q31-33 Locus Shows an Association between SNP variants in the IL-5 gene and Symptomatic Infection with the Human Blood Fluke, Schistosoma japonicum1 
Genetic studies of human susceptibility to Schistosoma (bloodfluke) infections have previously identified a genetic locus determining infection intensity with the African species, S. mansoni, in the 5q31-33 region of the human genome which is known to contain the Th2 immune response cluster including the genes encoding the IL-4, IL-5 and IL-13 cytokines. These cytokines are key players in inflammatory immune responses, and have previously been implicated in human susceptibility to infection with the Asian species, S. japonicum. In a nested case-control study, we genotyped 30 HapMap tagging SNPs across these three genes in 159 individuals identified as putatively susceptible to re-infection with S. japonicum and 133 putatively resistant individuals. A third group comprising 113 individuals susceptible to symptomatic infection was also included. The results provided no significant association at a global level between re-infection predisposition and any of the individual SNPs or haplotype blocks. However, two tagging SNPs in IL-5 demonstrated globally significant association with susceptibility to symptomatic infection. They were in strong linkage disequilibrium with each other and were found to belong to the same haplotype block which also provided a significant association after permutation testing. This haplotype was located in the 3’-UTR region of IL-5 suggesting that variants in this region of IL-5 may modulate the immune response in these individuals with symptomatic infection.
PMCID: PMC2757302  PMID: 18056382
Human; Parasitic-Helminth; Cytokines
9.  Common sequence variants on 20q11.22 confer melanoma susceptibility 
Nature genetics  2008;40(7):838-840.
We conducted a genome-wide association pooling study for cutaneous melanoma and performed validation in samples totalling 2019 cases and 2105 controls. Using pooling we identified a novel melanoma risk locus on chromosome 20 (rs910873, rs1885120), with replication in two further samples (combined P <1 × 10-15). The odds ratio is 1.75 (1.53, 2.01), with evidence for stronger association in early onset cases.
PMCID: PMC2755512  PMID: 18488026
10.  Variation in bone morphogenetic protein 15 is not associated with spontaneous human dizygotic twinning 
Human Reproduction (Oxford, England)  2008;23(10):2372-2379.
Spontaneous dizygotic (DZ) twinning in humans is under genetic control. In sheep, heterozygous loss of function mutations in bone morphogenetic protein 15 (BMP15) increase ovulation and hence twinning rates.
To investigate the role of BMP15 in human twinning, we typed 14 common variants, 4 rare novel variants initially detected by sequencing 279 mothers of DZ twins (MODZT) and 17 variants previously associated with premature ovarian failure (POF) in 933 DZ twinning families. We also typed five additional POF associated GDF9 variants.
There was some evidence for association between DZ twinning and a common intronic BMP15 variant (rs3897937), but this was not significant after correction for multiple testing. Three of the four novel variants (p.Pro174Ser, p.Ala311Thr and p.Arg392Thr) occurred in 1–5 MODZT but were not detected in 1512 controls. We also detected three POF associated mutations in both BMP15 and GDF9 at low frequencies in MODZT and controls.
We conclude that neither rare nor common BMP15 variants play a significant role in the variation in human DZ twinning.
PMCID: PMC2721723  PMID: 18614612
dizygotic twinning; BMP15; variation; genetic association; primary ovarian failure
11.  The search for genes contributing to endometriosis risk 
Human Reproduction Update  2008;14(5):447-457.
Genetic variation contributes to the risk of developing endometriosis. This review summarizes gene mapping studies in endometriosis and the prospects of finding gene pathways contributing to disease using the latest genome-wide strategies.
To identify candidate-gene association studies of endometriosis, a systematic literature search was conducted in PubMed of publications up to 1 April 2008, using the search terms ‘endometriosis’ plus ‘allele’ or ‘polymorphism’ or ‘gene’. Papers included were those with information on both case and control selection, showed allelic and/or genotypic results for named germ-line polymorphisms and were published in the English language.
Genetic variants in 76 genes have been examined for association, but none shows convincing evidence of replication in multiple studies. There is evidence for genetic linkage to chromosomes 7 and 10, but the genes (or variants) in these regions contributing to disease risk have yet to be identified. Genome-wide association is a powerful method that has been successful in locating genetic variants contributing to a range of common diseases. Several groups are planning these studies in endometriosis. For this to be successful, the endometriosis research community must work together to genotype sufficient cases, using clearly defined disease classifications, and conduct the necessary replication studies in several thousands of cases and controls.
Genes with convincing evidence for association with endometriosis are likely to be identified in large genome-wide studies. This will provide a starting point for functional and biological studies to develop better diagnosis and treatment for this debilitating disease.
PMCID: PMC2574950  PMID: 18535005
endometriosis; genetic variation; candidate gene; linkage; genome-wide association
12.  Common variation in the fibroblast growth factor receptor 2 gene is not associated with endometriosis risk 
Human Reproduction (Oxford, England)  2008;23(7):1661-1668.
Endometriosis is a polygenic disease with a complex and multifactorial aetiology that affects 8–10% of women of reproductive age. Epidemiological data support a link between endometriosis and cancers of the reproductive tract. Fibroblast growth factor receptor 2 (FGFR2) has recently been implicated in both endometrial and breast cancer. Our previous studies on endometriosis identified significant linkage to a novel susceptibility locus on chromosome 10q26 and the FGFR2 gene maps within this linkage region. We therefore hypothesized that variation in FGFR2 may contribute to the risk of endometriosis.
We genotyped 13 single nucleotide polymorphisms (SNPs) densely covering a 27 kb region within intron 2 of FGFR2 including two SNPs (rs2981582 and rs1219648) significantly associated with breast cancer and a total 40 tagSNPs across 150 kb of the FGFR2 gene. SNPs were genotyped in 958 endometriosis cases and 959 unrelated controls.
We found no evidence for association between endometriosis and FGFR2 intron 2 SNPs or SNP haplotypes and no evidence for association between endometriosis and variation across the FGFR2 gene.
Common variation in the breast-cancer implicated intron 2 and other highly plausible causative candidate regions of FGFR2 do not appear to be a major contributor to endometriosis susceptibility in our large Australian sample.
PMCID: PMC2902840  PMID: 18285324
endometriosis; fibroblast growth factor receptor 2; single nucleotide polymorphism; haplotype
13.  The Search for Genes Contributing to Endometriosis Risk 
Human reproduction update  2008;14(5):447-457.
Evidence from a range of studies suggests genetic variation contributes to the risk of developing endometriosis. Gene mapping studies therefore provide an important alternative to biological studies for determining pathways and mechanisms of disease. This review summarises current studies on genetic variation contributing to endometriosis and the prospects of finding gene pathways contributing to disease using the latest developments in gene mapping technology. Genetic variants in more than 59 genes have been examined for association with the disease, but there are no candidates with convincing evidence of replication in multiple study populations. There is evidence for genetic linkage to regions on chromosomes 7 and 10, but the genes (or variants) in these regions contributing to disease risk have yet to be identified.
Genome wide association studies using dense sets of up 1 one million markers spread across the genome have become possible with advances in technology. This is a powerful method that has been successful in locating genetic variants contributing to a range of common diseases. Several groups are planning these studies in endometriosis. For this to be successful we must follow the lead of studies in other diseases. The endometriosis research community must work together to fund the necessary genotyping and replication studies in several thousands of cases and controls. Convincing evidence for genes associated with endometriosis will provide the starting point for functional and biological studies to develop better diagnosis and treatment for this debilitating disease.
PMCID: PMC2574950  PMID: 18535005
Endometriosis; genetic variation; candidate gene; linkage; genome wide association
14.  A Genome-Wide Association Study Identifies Novel Alleles Associated with Hair Color and Skin Pigmentation 
PLoS Genetics  2008;4(5):e1000074.
We conducted a multi-stage genome-wide association study of natural hair color in more than 10,000 men and women of European ancestry from the United States and Australia. An initial analysis of 528,173 single nucleotide polymorphisms (SNPs) genotyped on 2,287 women identified IRF4 and SLC24A4 as loci highly associated with hair color, along with three other regions encompassing known pigmentation genes. We confirmed these associations in 7,028 individuals from three additional studies. Across these four studies, SLC24A4 rs12896399 and IRF4 rs12203592 showed strong associations with hair color, with p = 6.0×10−62 and p = 7.46×10−127, respectively. The IRF4 SNP was also associated with skin color (p = 6.2×10−14), eye color (p = 6.1×10−13), and skin tanning response to sunlight (p = 3.9×10−89). A multivariable analysis pooling data from the initial GWAS and an additional 1,440 individuals suggested that the association between rs12203592 and hair color was independent of rs1540771, a SNP between the IRF4 and EXOC2 genes previously found to be associated with hair color. After adjustment for rs12203592, the association between rs1540771 and hair color was not significant (p = 0.52). One variant in the MATP gene was associated with hair color. A variant in the HERC2 gene upstream of the OCA2 gene showed the strongest and independent association with hair color compared with other SNPs in this region, including three previously reported SNPs. The signals detected in a region around the MC1R gene were explained by MC1R red hair color alleles. Our results suggest that the IRF4 and SLC24A4 loci are associated with human hair color and skin pigmentation.
Author Summary
It has been a longstanding hypothesis that human pigmentation is tightly regulated by genetic variation. However, very few genes have been identified that contain common genetic variants associated with human pigmentation. We scanned the genome for genetic variants associated with natural hair color and other pigmentary characteristics in a multi-stage study of more than 10,000 men and women of European ancestry from the United States and Australia. We identified IRF4 and SLC24A4 as loci highly associated with hair color, along with three other regions encompassing known pigmentation genes. Further work is needed to identify the causal variants at these loci. Improved understanding of the genetic determinants of human pigmentation may help identify the molecular mechanisms of pigmentation-associated conditions such as the tanning response and skin cancers.
PMCID: PMC2367449  PMID: 18483556
15.  Highly cost-efficient genome-wide association studies using DNA pools and dense SNP arrays 
Nucleic Acids Research  2008;36(6):e35.
Genome-wide association (GWA) studies to map genes for complex traits are powerful yet costly. DNA-pooling strategies have the potential to dramatically reduce the cost of GWA studies. Pooling using Affymetrix arrays has been proposed and used but the efficiency of these arrays has not been quantified. We compared and contrasted Affymetrix Genechip HindIII and Illumina HumanHap300 arrays on the same DNA pools and showed that the HumanHap300 arrays are substantially more efficient. In terms of effective sample size, HumanHap300-based pooling extracts >80% of the information available with individual genotyping (IG). In contrast, Genechip HindIII-based pooling only extracts ∼30% of the available information. With HumanHap300 arrays concordance with IG data is excellent. Guidance is given on best study design and it is shown that even after taking into account pooling error, one stage scans can be performed for >100-fold reduced cost compared with IG. With appropriately designed two stage studies, IG can provide confirmation of pooling results whilst still providing ∼20-fold reduction in total cost compared with IG-based alternatives. The large cost savings with Illumina HumanHap300-based pooling imply that future studies need only be limited by the availability of samples and not cost.
PMCID: PMC2346606  PMID: 18276640

Results 1-15 (15)