Publications by authors named "David L Duffy"

133 Publications

'Essential Tremor' Phenotype in FMR1 Premutation/Gray Zone Sibling Series: Exploring Possible Genetic Modifiers.

Twin Res Hum Genet 2021 04 24;24(2):95-102. Epub 2021 Mar 24.

Department of Medicine (Neuroscience), Monash University, Melbourne, Victoria, Australia.

Fragile X-associated tremor/ataxia syndrome (FXTAS) occurs in carriers of fragile X mental retardation 1 (FMR1) X-linked small CGG expansion (gray zone [GZ] and premutation [PM]) alleles, containing 41-200 repeats. Major features comprise kinetic tremor, gait ataxia, cognitive decline and cerebellar peduncular white matter lesions, but atypical/incomplete FXTAS may occur. We explored the possibility of polygenic effects modifying the FXTAS spectrum phenotypes. We used three motor scales and selected cognitive tests in a series of three males and three females from a single sibship carrying PM or GZ alleles (44 to 75 repeats). The molecular profiles from these siblings were determined by genomewide association study with single-nucleotide polymorphism (SNP) genotyping by Illumina Global Screening Array. Nonparametric linkage analysis was applied and Parkinson's disease (PD) polygenic risk scores (PRSs) were calculated for all the siblings, based on 107 known risk variants. All male and female siblings manifested similar kinetic tremor phenotypes. In contrast to FXTAS, they showed negligible gait ataxia, and few white matter lesions on MRI. Cognitive functioning was unaffected. Suggestive evidence of linkage to a broad region of the short arm of chromosome 10 was obtained, and median PD PRS for the sibship fell within the top 30% of a sample of over 500,000 UK and Australian controls. The genomewide study results are suggestive of modifying effects of genetic risk loci linked to PD, on the neurological phenotype of FMR1-CGG small expansion carriers, resulting in an oligosymptomatic kinetic tremor seen in FXTAS spectrum, but also consistent with essential tremor.
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http://dx.doi.org/10.1017/thg.2021.10DOI Listing
April 2021

Genome-wide association study in almost 195,000 individuals identifies 50 previously unidentified genetic loci for eye color.

Sci Adv 2021 Mar 10;7(11). Epub 2021 Mar 10.

Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.

Human eye color is highly heritable, but its genetic architecture is not yet fully understood. We report the results of the largest genome-wide association study for eye color to date, involving up to 192,986 European participants from 10 populations. We identify 124 independent associations arising from 61 discrete genomic regions, including 50 previously unidentified. We find evidence for genes involved in melanin pigmentation, but we also find associations with genes involved in iris morphology and structure. Further analyses in 1636 Asian participants from two populations suggest that iris pigmentation variation in Asians is genetically similar to Europeans, albeit with smaller effect sizes. Our findings collectively explain 53.2% (95% confidence interval, 45.4 to 61.0%) of eye color variation using common single-nucleotide polymorphisms. Overall, our study outcomes demonstrate that the genetic complexity of human eye color considerably exceeds previous knowledge and expectations, highlighting eye color as a genetically highly complex human trait.
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http://dx.doi.org/10.1126/sciadv.abd1239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946369PMC
March 2021

Germline variants are associated with increased primary melanoma tumor thickness at diagnosis.

Hum Mol Genet 2021 01;29(21):3578-3587

Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, 4006, Australia.

Germline genetic variants have been identified, which predispose individuals and families to develop melanoma. Tumor thickness is the strongest predictor of outcome for clinically localized primary melanoma patients. We sought to determine whether there is a heritable genetic contribution to variation in tumor thickness. If confirmed, this will justify the search for specific genetic variants influencing tumor thickness. To address this, we estimated the proportion of variation in tumor thickness attributable to genome-wide genetic variation (variant-based heritability) using unrelated patients with measured primary cutaneous melanoma thickness. As a secondary analysis, we conducted a genome-wide association study (GWAS) of tumor thickness. The analyses utilized 10 604 individuals with primary cutaneous melanoma drawn from nine GWAS datasets from eight cohorts recruited from the general population, primary care and melanoma treatment centers. Following quality control and filtering to unrelated individuals with study phenotypes, 8125 patients were used in the primary analysis to test whether tumor thickness is heritable. An expanded set of 8505 individuals (47.6% female) were analyzed for the secondary GWAS meta-analysis. Analyses were adjusted for participant age, sex, cohort and ancestry. We found that 26.6% (SE 11.9%, P = 0.0128) of variation in tumor thickness is attributable to genome-wide genetic variation. While requiring replication, a chromosome 11 locus was associated (P < 5 × 10-8) with tumor thickness. Our work indicates that sufficiently large datasets will enable the discovery of genetic variants associated with greater tumor thickness, and this will lead to the identification of host biological processes influencing melanoma growth and invasion.
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http://dx.doi.org/10.1093/hmg/ddaa222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788289PMC
January 2021

Genome-wide association study identifies 48 common genetic variants associated with handedness.

Nat Hum Behav 2021 01 28;5(1):59-70. Epub 2020 Sep 28.

Institute of Biological Psychiatry, Mental Health Services of Copenhagen, Copenhagen, Denmark.

Handedness has been extensively studied because of its relationship with language and the over-representation of left-handers in some neurodevelopmental disorders. Using data from the UK Biobank, 23andMe and the International Handedness Consortium, we conducted a genome-wide association meta-analysis of handedness (N = 1,766,671). We found 41 loci associated (P < 5 × 10) with left-handedness and 7 associated with ambidexterity. Tissue-enrichment analysis implicated the CNS in the aetiology of handedness. Pathways including regulation of microtubules and brain morphology were also highlighted. We found suggestive positive genetic correlations between left-handedness and neuropsychiatric traits, including schizophrenia and bipolar disorder. Furthermore, the genetic correlation between left-handedness and ambidexterity is low (r = 0.26), which implies that these traits are largely influenced by different genetic mechanisms. Our findings suggest that handedness is highly polygenic and that the genetic variants that predispose to left-handedness may underlie part of the association with some psychiatric disorders.
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http://dx.doi.org/10.1038/s41562-020-00956-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116623PMC
January 2021

Germline and somatic albinism variants in amelanotic/hypomelanotic melanoma: Increased carriage of TYR and OCA2 variants.

PLoS One 2020 23;15(9):e0238529. Epub 2020 Sep 23.

Dermatology Research Centre, The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, Qld, Australia.

Amelanotic/hypomelanotic melanoma is a clinicopathologic subtype with absent or minimal melanin. This study assessed previously reported coding variants in albinism genes (TYR, OCA2, TYRP1, SLC45A2, SLC24A5, LRMDA) and common intronic, regulatory variants of OCA2 in individuals with amelanotic/hypomelanotic melanoma, pigmented melanoma cases and controls. Exome sequencing was available for 28 individuals with amelanotic/hypomelanotic melanoma and 303 individuals with pigmented melanoma, which were compared to whole exome data from 1144 Australian controls. Microarray genotyping was available for a further 17 amelanotic/hypomelanotic melanoma, 86 pigmented melanoma, 147 melanoma cases (pigmentation unknown) and 652 unaffected controls. Rare deleterious variants in TYR/OCA1 were more common in amelanotic/hypomelanotic melanoma cases than pigmented melanoma cases (set mixed model association tests P = 0.0088). The OCA2 hypomorphic allele p.V443I was more common in melanoma cases (1.8%) than controls (1.0%, X2 P = 0.02), and more so in amelanotic/hypomelanotic melanoma (4.4%, X2 P = 0.007). No amelanotic/hypomelanotic melanoma cases carried an eye and skin darkening haplotype of OCA2 (including rs7174027), present in 7.1% of pigmented melanoma cases (P = 0.0005) and 9.4% controls. Variants in TYR and OCA2 may play a role in amelanotic/hypomelanotic melanoma susceptibility. We suggest that somatic loss of function at these loci could contribute to the loss of tumor pigmentation, consistent with this we found a higher rate of somatic mutation in TYR/OCA2 in amelanotic/hypomelanotic melanoma vs pigmented melanoma samples (28.6% vs 3.0%; P = 0.021) from The Cancer Genome Atlas Skin Cutaneous Melanoma collection.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238529PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510969PMC
October 2020

Multiplex melanoma families are enriched for polygenic risk.

Hum Mol Genet 2020 10;29(17):2976-2985

Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.

Cancers, including cutaneous melanoma, can cluster in families. In addition to environmental etiological factors such as ultraviolet radiation, cutaneous melanoma has a strong genetic component. Genetic risks for cutaneous melanoma range from rare, high-penetrance mutations to common, low-penetrance variants. Known high-penetrance mutations account for only about half of all densely affected cutaneous melanoma families, and the causes of familial clustering in the remainder are unknown. We hypothesize that some clustering is due to the cumulative effect of a large number of variants of individually small effect. Common, low-penetrance genetic risk variants can be combined into polygenic risk scores. We used a polygenic risk score for cutaneous melanoma to compare families without known high-penetrance mutations with unrelated melanoma cases and melanoma-free controls. Family members had significantly higher mean polygenic load for cutaneous melanoma than unrelated cases or melanoma-free healthy controls (Bonferroni-corrected t-test P = 1.5 × 10-5 and 6.3 × 10-45, respectively). Whole genome sequencing of germline DNA from 51 members of 21 families with low polygenic risk for melanoma identified a CDKN2A p.G101W mutation in a single family but no other candidate high-penetrance melanoma susceptibility genes. This work provides further evidence that melanoma, like many other common complex disorders, can arise from the joint action of multiple predisposing factors, including rare high-penetrance mutations, as well as via a combination of large numbers of alleles of small effect.
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http://dx.doi.org/10.1093/hmg/ddaa156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566496PMC
October 2020

Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility.

Nat Genet 2020 05 27;52(5):494-504. Epub 2020 Apr 27.

Department of Dermatology, Instituto Valenciano de Oncología, Valencia, Spain.

Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 × 10) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis.
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http://dx.doi.org/10.1038/s41588-020-0611-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255059PMC
May 2020

Variation at and Asthma on the Island of Tristan da Cunha.

Twin Res Hum Genet 2019 10 14;22(5):277-282. Epub 2019 Oct 14.

University of Toronto Asthma and Airway Centre, University Health Network, Toronto, ON, Canada.

A high prevalence of asthma has been documented among the inhabitants of Tristan da Cunha, an isolated island in the South Atlantic. The population derives from just 28 founders. We performed lung function testing, including methacholine inhalation challenge, allergen skin prick testing, and collected DNA from essentially all of the current island population (269 individuals), and genotyped a panel of 43 single-nucleotide polymorphisms (SNPs) reported as associated with asthma and atopy. We carried out a mixed-model association analysis using the known pedigree. There were 96 individuals diagnosed as asthmatic (36%), and heritability estimates were similar to those from nonisolated population samples (multifactorial threshold model, h2 = 48%). The first component from a genetic principal components analysis using the entire SNP panel was nonlinearly associated with asthma, with the maximum risk to those intermediate to reference (Human Genome Diversity Project) European and African samples means. The single most strongly associated SNP was rs2786098 (p = 5.5 × 10-5), known to regulate the gene DENND1B. This explained approximately one-third of the trait heritability, with an allelic odds ratio for the A allele of 2.6. Among A/A carriers, 10 out of 12 individuals were asthmatic. The rs2786098*A variant was initially reported to decrease the risk of childhood (atopic) asthma in European but slightly increase the risk in African-descended populations, and does significantly alter Th2 cell function. Despite an absence of overall association with this variant in recent asthma genome wide association studies meta-analyses, an effect may exist on the particular genetic background of the Tristan da Cunha population.
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http://dx.doi.org/10.1017/thg.2019.82DOI Listing
October 2019

Genes Determining Nevus Count and Dermoscopic Appearance in Australian Melanoma Cases and Controls.

J Invest Dermatol 2020 02 15;140(2):498-501.e17. Epub 2019 Aug 15.

Dermatology Research Centre, The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, Australia. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2019.05.032DOI Listing
February 2020

IRF4 rs12203592*T/T genotype is associated with nodular melanoma.

Melanoma Res 2019 08;29(4):445-446

Dermatology Research Centre, The University of Queensland Diamantina Institute.

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http://dx.doi.org/10.1097/CMR.0000000000000596DOI Listing
August 2019

Noncoding Variations in the Gene Encoding Ceramide Synthase 6 are Associated with Type 2 Diabetes in a Large Indigenous Australian Pedigree.

Twin Res Hum Genet 2019 04 23;22(2):79-87. Epub 2019 Apr 23.

Diabetes Research Laboratories, School of Clinical Medicine Prince Charles Hospital Northside Clinical Unit, Faculty of Medicine,University of Queensland,Brisbane,Queensland,Australia.

Type 2 diabetes (T2D) is a chronic disease that disproportionately affects Indigenous Australians. We have previously reported the localization of a novel T2D locus by linkage analysis to chromosome 2q24 in a large admixed Indigenous Australian pedigree (Busfield et al. (2002). American Journal of Human Genetics, 70, 349-357). Here we describe fine mapping of this region in this pedigree, with the identification of SNPs showing strong association with T2D: rs3845724 (diabetes p = 7 × 10-4), rs4668106 (diabetes p = 9 × 10-4) and rs529002 (plasma glucose p = 3 × 10-4). These associations were successfully replicated in an independent collection of Indigenous Australian T2D cases and controls. These SNPs all lie within the gene encoding ceramide synthase 6 (CERS6) and thus may regulate ceramide synthesis.
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http://dx.doi.org/10.1017/thg.2019.13DOI Listing
April 2019

Publisher Correction: Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways.

Nat Commun 2019 01 14;10(1):299. Epub 2019 Jan 14.

Dermatology Research Centre, University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia.

The original version of this Article contained errors in the spelling of the authors Fan Liu and M. Arfan Ikram, which were incorrectly given as Fan Lui and Arfan M. Ikram. In addition, the original version of this Article also contained errors in the author affiliations which are detailed in the associated Publisher Correction.
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http://dx.doi.org/10.1038/s41467-018-08078-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331636PMC
January 2019

Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways.

Nat Commun 2018 11 14;9(1):4774. Epub 2018 Nov 14.

Dermatology Research Centre, University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia.

The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, UK, and USA comprising 52,506 individuals. We confirm known loci including MTAP, PLA2G6, and IRF4, and detect novel SNPs in KITLG and a region of 9q32. In a bivariate analysis combining the nevus results with a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1, PPARGC1B, HDAC4, FAM208B, DOCK8, and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level. Overall, we conclude that most nevus genes affect melanoma risk (KITLG an exception), while many melanoma risk loci do not alter nevus count. For example, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis.
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http://dx.doi.org/10.1038/s41467-018-06649-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235897PMC
November 2018

Cell-type-specific eQTL of primary melanocytes facilitates identification of melanoma susceptibility genes.

Genome Res 2018 11 17;28(11):1621-1635. Epub 2018 Oct 17.

Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

Most expression quantitative trait locus (eQTL) studies to date have been performed in heterogeneous tissues as opposed to specific cell types. To better understand the cell-type-specific regulatory landscape of human melanocytes, which give rise to melanoma but account for <5% of typical human skin biopsies, we performed an eQTL analysis in primary melanocyte cultures from 106 newborn males. We identified 597,335 -eQTL SNPs prior to linkage disequilibrium (LD) pruning and 4997 eGenes (FDR < 0.05). Melanocyte eQTLs differed considerably from those identified in the 44 GTEx tissue types, including skin. Over a third of melanocyte eGenes, including key genes in melanin synthesis pathways, were unique to melanocytes compared to those of GTEx skin tissues or TCGA melanomas. The melanocyte data set also identified -eQTLs, including those connecting a pigmentation-associated functional SNP with four genes, likely through -regulation of Melanocyte eQTLs are enriched in -regulatory signatures found in melanocytes as well as in melanoma-associated variants identified through genome-wide association studies. Melanocyte eQTLs also colocalized with melanoma GWAS variants in five known loci. Finally, a transcriptome-wide association study using melanocyte eQTLs uncovered four novel susceptibility loci, where imputed expression levels of five genes (, , , , and ) were associated with melanoma at genome-wide significant -values. Our data highlight the utility of lineage-specific eQTL resources for annotating GWAS findings, and present a robust database for genomic research of melanoma risk and melanocyte biology.
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http://dx.doi.org/10.1101/gr.233304.117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6211648PMC
November 2018

'Mind your Moles' study: protocol of a prospective cohort study of melanocytic naevi.

BMJ Open 2018 09 19;8(9):e025857. Epub 2018 Sep 19.

Cancer and Population Studies, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

Introduction: Having many melanocytic naevi or 'moles' on the skin is the strongest predictor of melanoma; thus, much can be learnt from investigating naevi in the general population. We aim to improve the understanding of the epidemiology and biology of naevi by conducting a 3-year prospective study of melanocytic naevi in adults.

Methods And Analysis: This is a population-based cohort study of melanocytic naevi in 200 adults aged 20-69 years recruited via the Australian electoral roll. At baseline, participants will complete a questionnaire on their sun behaviour and health and undergo a clinical examination. Three-dimensional (3D) total-body photography will be used to record the images of skin lesions. Pigmented naevi will be analysed in terms of number, diameter, colour and border irregularity using automated analysis software (excluding scalp, beneath underwear and soles of feet). All naevi ≥5 mm will be recorded using the integrated dermoscopy photographic system. A saliva sample will be obtained at baseline for genomic DNA analysis of pigmentation, naevus and melanoma-associated genes using the Illumina HumanCoreExome platform. The sun behaviour and health follow-up questionnaire, clinical examination and 3D total-body photography will be repeated every 6 months for 3 years. The first 50 participants will also undergo manual counts of naevi ≥2 mm and ≥5 mm at baseline, 6-month and 12-month follow-ups. Microbiopsy and excision of naevi of research interest is planned to commence at the 18-month time point among those who agree to donate samples for detailed histopathological and molecular assessment.

Ethics And Dissemination: This study was approved by the Metro South Health Human Research Ethics Committee in April 2016 (approval number: HREC/16/QPAH/125). The findings will be disseminated through peer-reviewed and non-peer-reviewed publications and presentations at conferences.
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http://dx.doi.org/10.1136/bmjopen-2018-025857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6150134PMC
September 2018

The Relationship Between Personality and Somatic and Psychological Distress: A Comparison of Chinese and Australian Adolescents.

Behav Genet 2018 07 5;48(4):315-322. Epub 2018 Jun 5.

Tianjin University, Tianjin, People's Republic of China.

The extent to which correlations between personality domains and physical and psychological health generalize cross-culturally is unclear. We compared the strength of associations between the personality domains and somatic and psychological distress in Chinese (N = 2069) and a genetically informative sample of Australian (N = 2936) adolescents. We also examined the genetic and environmental etiology between personality, somatic and psychological distress in an Australian sample of 390 monozygotic twins and 698 dizygotic twins. In both populations, personality was assessed using the Junior Eysenck Personality Questionnaire. Somatic and psychological distress was assessed using the Somatic and Psychological Health Report. We found significant cultural differences in the relationship between adolescents' personality traits and somatic and psychological distress. Extraversion was positively associated with somatic distress in the Chinese but not in Australian adolescents. In the Australian twins, genetic covariation between neuroticism and somatic and psychological distress was stronger compared to the genetic associations between either psychoticism or extraversion with psychological distress.
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http://dx.doi.org/10.1007/s10519-018-9905-3DOI Listing
July 2018

Accuracy of Inferred APOE Genotypes for a Range of Genotyping Arrays and Imputation Reference Panels.

J Alzheimers Dis 2018 ;64(1):49-54

QIMR Berghofer Medical Research Institute, Brisbane, Australia.

Cohort studies investigating aging and dementia require APOE genotyping. We compared directly measured APOE genotypes to 'hard-call' genotypes derived from imputing genome-wide genotyping data from a range of platforms using several imputation panels. Older GWAS arrays imputed to 1000 Genomes Project (1KGP) phases and the Haplotype Reference Consortium (HRC) reference panels were able to achieve concordance rates of over 98% with stringent quality control (hard-call-threshold 0.8). However, this resulted in high levels of missingness (>12% with 1KGP and 5% with HRC). With recent GWAS arrays, concordance of 99% could be obtained with relatively lenient QC, resulting in no missingness.
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http://dx.doi.org/10.3233/JAD-171104DOI Listing
June 2019

Genome-wide association study in 176,678 Europeans reveals genetic loci for tanning response to sun exposure.

Nat Commun 2018 05 8;9(1):1684. Epub 2018 May 8.

Department of Twin Research and Genetic Epidemiology, King's College London, London, SE1 7EH, UK.

The skin's tendency to sunburn rather than tan is a major risk factor for skin cancer. Here we report a large genome-wide association study of ease of skin tanning in 176,678 subjects of European ancestry. We identify significant association with tanning ability at 20 loci. We confirm previously identified associations at six of these loci, and report 14 novel loci, of which ten have never been associated with pigmentation-related phenotypes. Our results also suggest that variants at the AHR/AGR3 locus, previously associated with cutaneous malignant melanoma the underlying mechanism of which is poorly understood, might act on disease risk through modulation of tanning ability.
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http://dx.doi.org/10.1038/s41467-018-04086-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940788PMC
May 2018

Genome-wide association meta-analysis of individuals of European ancestry identifies new loci explaining a substantial fraction of hair color variation and heritability.

Nat Genet 2018 05 16;50(5):652-656. Epub 2018 Apr 16.

Centre for Ophthalmology and Visual Science, University of Western Australia, Lions Eye Institute, Perth, WA, Australia.

Hair color is one of the most recognizable visual traits in European populations and is under strong genetic control. Here we report the results of a genome-wide association study meta-analysis of almost 300,000 participants of European descent. We identified 123 autosomal and one X-chromosome loci significantly associated with hair color; all but 13 are novel. Collectively, single-nucleotide polymorphisms associated with hair color within these loci explain 34.6% of red hair, 24.8% of blond hair, and 26.1% of black hair heritability in the study populations. These results confirm the polygenic nature of complex phenotypes and improve our understanding of melanin pigment metabolism in humans.
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http://dx.doi.org/10.1038/s41588-018-0100-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935237PMC
May 2018

Towards the full spectrum of genes for human skin colour.

Pigment Cell Melanoma Res 2018 07 26;31(4):457-458. Epub 2018 Feb 26.

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http://dx.doi.org/10.1111/pcmr.12691DOI Listing
July 2018

Acquired melanocytic naevus phenotypes and genotypes in Han Chinese: a cross-sectional study.

PeerJ 2017 20;5:e4168. Epub 2017 Dec 20.

Dermatology Research Centre, The University of Queensland Diamantina Institute, Brisbane, Queensland, Australia.

Background: Early detection and treatment are the most important elements in reducing the incidence of melanoma deaths. Acquired melanocytic naevi (AMN) are well-known precursors of melanoma but most of our knowledge on the clinico-dermoscopic phenotypes of AMN is based on studies in European-background populations, particularly American and Australian populations. There has been little research in Chinese Han populations on clinico-dermoscopic variability of naevi or how naevi are affected by melanoma-linked variants of the melanocortin 1 receptor () gene.

Methods: Clinical and dermoscopic features of 448 AMN in 115 patients from the Han ethnic group in mainland China were described. Germline polymorphisms in were determined for 98 of these patients.

Results: AMN were predominantly found on the head and neck. Dermoscopic patterns observed were nonspecific, reticular, globular, and parallel furrow, with most AMN having a nonspecific pattern. There were no associations between polymorphisms and clinical or dermoscopic features of AMN.

Discussion: Our results provide evidence that AMN in the Han population in China have similar dermoscopic patterns to those in European populations, but are present in much lower numbers. As there were no associations between clinical or dermoscopic features of AMN and polymorphisms, further studies should focus on candidate gene associations with AMN features and the risk of melanoma, with larger sample sizes and comparisons to AMN in other populations.
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http://dx.doi.org/10.7717/peerj.4168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741976PMC
December 2017

Shared genetic origin of asthma, hay fever and eczema elucidates allergic disease biology.

Nat Genet 2017 Dec 30;49(12):1752-1757. Epub 2017 Oct 30.

Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia.

Asthma, hay fever (or allergic rhinitis) and eczema (or atopic dermatitis) often coexist in the same individuals, partly because of a shared genetic origin. To identify shared risk variants, we performed a genome-wide association study (GWAS; n = 360,838) of a broad allergic disease phenotype that considers the presence of any one of these three diseases. We identified 136 independent risk variants (P < 3 × 10), including 73 not previously reported, which implicate 132 nearby genes in allergic disease pathophysiology. Disease-specific effects were detected for only six variants, confirming that most represent shared risk factors. Tissue-specific heritability and biological process enrichment analyses suggest that shared risk variants influence lymphocyte-mediated immunity. Six target genes provide an opportunity for drug repositioning, while for 36 genes CpG methylation was found to influence transcription independently of genetic effects. Asthma, hay fever and eczema partly coexist because they share many genetic risk variants that dysregulate the expression of immune-related genes.
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http://dx.doi.org/10.1038/ng.3985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989923PMC
December 2017

Classifying dermoscopic patterns of naevi in a case-control study of melanoma.

PLoS One 2017 17;12(10):e0186647. Epub 2017 Oct 17.

Dermatology Research Centre, The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia.

Changes in dermoscopic patterns of naevi may be associated with melanoma; however, there is no consensus on which dermoscopic classification system is optimal. To determine whether different classification systems give comparable results and can be combined for analysis, we applied two systems to a case-control study of melanoma with 1037 participants: 573 classified using a "1/3 major feature" system, 464 classified based on rules of appearance, and 263 classified with both criteria. There was strong correlation for non-specific (Spearman R = 0.96) and reticular (Spearman R = 0.82) naevi, with a slight bias for globular naevi with the rules of appearance system. Inter-observer reliability was high for the rules of appearance system, particularly for reticular naevi (Pearson >0.97). We show that different classification systems for naevi can be combined for data analysis, and describe a method for determining what adjustments may need to be applied to combine data sets.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0186647PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5645144PMC
October 2017

Genome-Wide Association Shows that Pigmentation Genes Play a Role in Skin Aging.

J Invest Dermatol 2017 09 11;137(9):1887-1894. Epub 2017 May 11.

QIMR Berghofer Medical Research Institute, Brisbane, Australia.

Loss of fine skin patterning is a sign of both aging and photoaging. Studies investigating the genetic contribution to skin patterning offer an opportunity to better understand a trait that influences both physical appearance and risk of keratinocyte skin cancer. We undertook a meta-analysis of genome-wide association studies of a measure of skin pattern (microtopography score) damage in 1,671 twin pairs and 1,745 singletons (N = 5,087) drawn from three independent cohorts. We identified that rs185146 near SLC45A2 is associated with a skin aging trait at genome-wide significance (P = 4.1 × 10); to our knowledge this is previously unreported. We also confirm previously identified loci, rs12203592 near IRF4 (P = 8.8 × 10) and rs4268748 near MC1R (P = 1.2 × 10). At all three loci we highlight putative functionally relevant SNPs. There are a number of red hair/low pigmentation alleles of MC1R; we found that together these MC1R alleles explained 4.1% of variance in skin pattern damage. We also show that skin aging and reported experience of sunburns was proportional to the degree of penetrance for red hair of alleles of MC1R. Our work has uncovered genetic contributions to skin aging and confirmed previous findings, showing that pigmentation is a critical determinant of skin aging.
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http://dx.doi.org/10.1016/j.jid.2017.04.026DOI Listing
September 2017

Cysteinyl Leukotrienes Pathway Genes, Atopic Asthma and Drug Response: From Population Isolates to Large Genome-Wide Association Studies.

Front Pharmacol 2016 1;7:299. Epub 2016 Dec 1.

QIMR Berghofer Medical Research Institute, Herston QLD, Australia.

Genetic variants associated with asthma pathogenesis and altered response to drug therapy are discussed. Many studies implicate polymorphisms in genes encoding the enzymes responsible for leukotriene synthesis and intracellular signaling through activation of seven transmembrane domain receptors, such as the cysteinyl leukotriene 1 (CYSLTR1) and 2 (CYSLTR2) receptors. The leukotrienes are polyunsaturated lipoxygenated eicosatetraenoic acids that exhibit a wide range of pharmacological and physiological actions. Of the three enzymes involved in the formation of the leukotrienes, arachidonate 5 lipoxygenase 5 (ALOX5), leukotriene C4 synthase (LTC4S), and leukotriene hydrolase (LTA4H) are all polymorphic. These polymorphisms often result in variable production of the CysLTs (LTC4, LTD4, and LTE4) and LTB4. Variable number tandem repeat sequences located in the Sp1-binding motif within the promotor region of the gene are associated with leukotriene burden and bronchoconstriction independent of asthma risk. A 444A > C SNP polymorphism in the gene, encoding an enzyme required for the formation of a glutathione adduct at the C-6 position of the arachidonic acid backbone, is associated with severe asthma and altered response to the CYSLTR1 receptor antagonist zafirlukast. Genetic variability in the CysLT pathway may contribute additively or synergistically to altered drug responses. The 601 A > G variant of the gene, encoding the Met201Val receptor variant, is associated with atopic asthma in the general European population, where it is present at a frequency of ∼2.6%. The variant was originally found in the founder population of Tristan da Cunha, a remote island in the South Atlantic, in which the prevalence of atopy is approximately 45% and the prevalence of asthma is 36%. work showed that the atopy-associated Met201Val variant was inactivating with respect to ligand binding, Ca flux and inositol phosphate generation. In addition, the gene, located at Xq13-21.1, has been associated with atopic asthma. The activating Gly300Ser CYSLTR1 variant is discussed. In addition to genetic loci, risk for asthma may be influenced by environmental factors such as smoking. The contribution of CysLT pathway gene sequence variants to atopic asthma is discussed in the context of other genes and environmental influences known to influence asthma.
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http://dx.doi.org/10.3389/fphar.2016.00299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5131607PMC
December 2016

Analysis of Quantitative Trait Loci.

Authors:
David L Duffy

Methods Mol Biol 2017 ;1526:191-203

Genetic Epidemiology Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Rd., Brisbane, QLD, 4006, Australia.

Although the term quantitative trait locus (QTL) strictly refers merely to a genetic variant that causes changes in a quantitative phenotype such as height, QTL analysis more usually describes techniques used to study oligogenic or polygenic traits where each identified locus contributes a relatively small amount to the genetic determination of the trait, which may be categorical in nature. Originally, too, it would be clear that it covered segregation and genetic linkage analysis, but now genetic association analysis in a genome-wide SNP or sequencing experiment would be the commonest application. The same biometrical genetic statistical apparatus used in this setting-analysis of variance, linear or generalized linear mixed models-can actually be applied to categorical phenotypes, as well as to multiple traits simultaneously, dealing with and taking advantage of genetic pleiotropy. Most recently, they are being used to make inferences about population and evolutionary genetics, with applications ranging from human disease to control of disease-causing organisms. Several computer software packages make it relatively straightforward to fit these statistically complex models to the large amounts of genotype and phenotype data routinely collected today.
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http://dx.doi.org/10.1007/978-1-4939-6613-4_11DOI Listing
January 2018

Familial aggregation of albuminuria and arterial hypertension in an Aboriginal Australian community and the contribution of variants in ACE and TP53.

BMC Nephrol 2016 11 21;17(1):183. Epub 2016 Nov 21.

Centre for Chronic Disease, The University of Queensland School of Medicine, Brisbane, Australia.

Background: Aboriginal Australians are at high risk of cardiovascular, metabolic and renal diseases, resulting in a marked reduction in life expectancy when compared to the rest of the Australian population. This is partly due to recognized environmental and lifestyle risk factors, but a contribution of genetic susceptibility is also likely.

Methods: Using results from a comprehensive survey of one community (N = 1350 examined individuals), we have tested for familial aggregation of plasma glucose, arterial blood pressure, albuminuria (measured as urinary albumin to creatinine ratio, UACR) and estimated glomerular filtration rate (eGFR), and quantified the contribution of variation at four candidate genes (ACE; TP53; ENOS3; MTHFR).

Results: In the subsample of 357 individuals with complete genotype and phenotype data we showed that both UACR (h = 64%) and blood pressure (sBP h = 29%, dBP, h = 11%) were significantly heritable. The ACE insertion-deletion (P = 0.0009) and TP53 codon72 polymorphisms (P = 0.003) together contributed approximately 15% of the total heritability of UACR, with an effect of ACE genotype on BP also clearly evident.

Conclusions: While the effects of the ACE insertion-deletion on risk of renal disease (especially in the setting of diabetes) are well recognized, this is only the second study to implicate p53 genotype as a risk factor for albuminuria - the other being an earlier study we performed in a different Aboriginal community (McDonald et al., J Am Soc Nephrol 13: 677-83, 2002). We conclude that there are significant genetic contributions to the high prevalence of chronic diseases observed in this population.
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http://dx.doi.org/10.1186/s12882-016-0396-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5117595PMC
November 2016

GSTP1 does not modify MC1R effects on melanoma risk.

Exp Dermatol 2017 08 23;26(8):730-733. Epub 2017 Mar 23.

Dermatology Research Centre, The University of Queensland School of Medicine, Translational Research Institute, Brisbane, Qld, Australia.

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http://dx.doi.org/10.1111/exd.13114DOI Listing
August 2017
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