Allan F McRae

Publications of Allan F McRae

• The brisbane systems genetics study: genetical genomics meets complex trait genetics.

  Authors: Joseph E Powell, Anjali K Henders, Allan F McRae, Anthony Caracella, Sara Smith, Margaret J Wright, John B Whitfield, Emmanouil T Dermitzakis, Nicholas G Martin, Peter M Visscher, Grant W Montgomery

  PloS one. 01/2012; 7(4):e35430.

  There is growing evidence that genetic risk factors for common disease are caused by hereditary changes of gene regulation acting in complex pathways. Clearly understanding the molecular geneticThere is growing evidence that genetic risk factors for common disease are caused by hereditary changes of gene regulation acting in complex pathways. Clearly understanding the molecular genetic relationships between genetic control of gene expression and its effect on complex diseases is essential. Here we describe the Brisbane Systems Genetics Study (BSGS), a family-based study that will be used to elucidate the genetic factors affecting gene expression and the role of gene regulation in mediating endophenotypes and complex diseases.BSGS comprises of a total of 962 individuals from 314 families, for which we have high-density genotype, gene expression and phenotypic data. Families consist of combinations of both monozygotic and dizygotic twin pairs, their siblings, and, for 72 families, both parents. A significant advantage of the inclusion of parents is improved power to disentangle environmental, additive genetic and non-additive genetic effects of gene expression and measured phenotypes. Furthermore, it allows for the estimation of parent-of-origin effects, something that has not previously been systematically investigated in human genetical genomics studies. Measured phenotypes available within the BSGS include blood phenotypes and biochemical traits measured from components of the tissue sample in which transcription levels are determined, providing an ideal test case for systems genetics approaches.We report results from an expression quantitative trait loci (eQTL) analysis using 862 individuals from BSGS to test for associations between expression levels of 17,926 probes and 528,509 SNP genotypes. At a study wide significance level approximately 15,000 associations were observed between expression levels and SNP genotypes. These associations corresponded to a total of 2,081 expression quantitative trait loci (eQTL) involving 1,503 probes. The majority of identified eQTL (87%) were located within cis-regions.

• Genetic control of gene expression in whole blood and lymphoblastoid cell lines is largely independent.

  Authors: Joseph E Powell, Anjali K Henders, Allan F McRae, Margaret J Wright, Nicholas G Martin, Emmanouil T Dermitzakis, Grant W Montgomery, Peter M Visscher

  Genome research. 12/2011; 22(3):456-66.

  The degree to which the level of genetic variation for gene expression is shared across multiple tissues has important implications for research investigating the role of expression on the etiologyThe degree to which the level of genetic variation for gene expression is shared across multiple tissues has important implications for research investigating the role of expression on the etiology of complex human traits and diseases. In the last few years, several studies have been published reporting the extent of overlap in expression quantitative trait loci (eQTL) identified in multiple tissues or cell types. Although these studies provide important information on the regulatory control of genes across tissues, their limited power means that they can typically only explain a small proportion of genetic variation for gene expression. Here, using expression data from monozygotic twins (MZ), we investigate the genetic control of gene expression in lymphoblastoid cell lines (LCL) and whole blood (WB). We estimate the genetic correlation that represents the combined effects of all causal loci across the whole genome and is a measure of the level of common genetic control of gene expression between the two RNA sources. Our results show that, when averaged across the genome, mean levels of genetic correlation for gene expression in LCL and WB samples are close to zero. We support our results with evidence from gene expression in an independent sample of LCL, T-cells, and fibroblasts. In addition, we provide evidence that housekeeping genes, which maintain basic cellular functions, are more likely to have high genetic correlations between the RNA sources than non-housekeeping genes, implying a relationship between the transcript function and the degree to which a gene has tissue-specific genetic regulatory control.

• Association between ORMDL3, IL1RL1 and a deletion on chromosome 17q21 with asthma risk in Australia.

  Authors: Manuel A R Ferreira, Allan F McRae, Sarah E Medland, Dale R Nyholt, Scott D Gordon, Margaret J Wright, Anjali K Henders, Pamela A Madden, Peter M Visscher, Naomi R Wray, Andrew C Heath, Grant W Montgomery, David L Duffy, Nicholas G Martin

  European journal of human genetics : EJHG. 10/2011; 19(10):1109.

• Variation in BMPR1B, TGFRB1 and BMPR2 and control of dizygotic twinning.

  Authors: Hien T T Luong, Justin Chaplin, Allan F McRae, Sarah E Medland, Gonneke Willemsen, Dale R Nyholt, Anjali K Henders, Chantal Hoekstra, David L Duffy, Nicholas G Martin, Dorret I Boomsma, Grant W Montgomery, Jodie N Painter

  Twin research and human genetics : the official journal of the International Society for Twin Studies. 10/2011; 14(5):408-16.

  Genes in the TGF9 signaling pathway play important roles in the regulation of ovarian follicle growth and ovulation rate. Mutations in three genes in this pathway, growth differentiation factor 9Genes in the TGF9 signaling pathway play important roles in the regulation of ovarian follicle growth and ovulation rate. Mutations in three genes in this pathway, growth differentiation factor 9 (GDF9), bone morphogenetic protein 15 (BMP15) and the bone morphogenetic protein receptor B 1 (BMPRB1), influence dizygotic (DZ) twinning rates in sheep. To date, only variants in GDF9 and BMP15, but not their receptors transforming growth factor ß receptor 1 (TGFBR1), bone morphogenetic protein receptor 2 (BMPR2) and BMPR1B, have been investigated with respect to their roles in human DZ twinning. We screened for rare and novel variants in TGFBR1, BMPR2 and BMPR1B in mothers of dizygotic twins (MODZT) from twin-dense families, and assessed association between genotyped and imputed variants and DZ twinning in another large sample of MODZT. Three novel variants were found: a deep intronic variant in BMPR2, and one intronic and one non-synonymous exonic variant in BMPRB1 which would result in the replacement of glutamine by glutamic acid at amino acid position 294 (p.Gln294Glu). None of these variants were predicted to have major impacts on gene function. However, the p.Gln294Glu variant changes the same amino acid as a sheep BMPR1B functional variant and may have functional consequences. Six BMPR1B variants were marginally associated with DZ twinning in the larger case-control sample, but these were no longer significant once multiple testing was taken into account. Our results suggest that variation in the TGF9 signaling pathway type II receptors has limited effects on DZ twinning rates in humans.

• GWAS findings for human iris patterns: associations with variants in genes that influence normal neuronal pattern development.

  Authors: Mats Larsson, David L Duffy, Gu Zhu, Jimmy Z Liu, Stuart Macgregor, Allan F McRae, Margaret J Wright, Richard A Sturm, David A Mackey, Grant W Montgomery, Nicholas G Martin, Sarah E Medland

  American journal of human genetics. 08/2011; 89(2):334-43.

  Human iris patterns are highly variable. The origins of this variation are of interest in the study of iris-related eye diseases and forensics, as well as from an embryological developmentalHuman iris patterns are highly variable. The origins of this variation are of interest in the study of iris-related eye diseases and forensics, as well as from an embryological developmental perspective, with regard to their possible relationship to fundamental processes of neurodevelopment. We have performed genome-wide association scans on four iris characteristics (crypt frequency, furrow contractions, presence of peripupillary pigmented ring, and number of nevi) in three Australian samples of European descent. Both the discovery (n = 2121) and replication (n = 499 and 73) samples showed evidence for association between (1) crypt frequency and variants in the axonal guidance gene SEMA3A (p = 6.6 × 10(-11)), (2) furrow contractions and variants within the cytoskeleton gene TRAF3IP1 (p = 2.3 × 10(-12)), and (3) the pigmented ring and variants in the well-known pigmentation gene SLC24A4 (p = 7.6 × 10(-21)). These replicated findings individually accounted for around 1.5%-3% of the variance for these iris characteristics. Because both SEMA3A and TRAFIP1 are implicated in pathways that control neurogenesis, neural migration, and synaptogenesis, we also examined the evidence of enhancement among such genes, finding enrichment for crypts and furrows. These findings suggest that genes involved in normal neuronal pattern development may also influence tissue structures in the human iris.

• Clustered coding variants in the glutamate receptor complexes of individuals with schizophrenia and bipolar disorder.

  Authors: René A W Frank, Allan F McRae, Andrew J Pocklington, Louie N van de Lagemaat, Pau Navarro, Mike D R Croning, Noboru H Komiyama, Sophie J Bradley, R A John Challiss, J Douglas Armstrong [......] Sarah E Hunt, Alison J Coffey, Venkatesh Ranganath, Panos Deloukas, Jane Rogers, Walter J Muir, Ian J Deary, Douglas H Blackwood, Peter M Visscher, Seth G N Grant

  PloS one. 01/2011; 6(4):e19011.

  Current models of schizophrenia and bipolar disorder implicate multiple genes, however their biological relationships remain elusive. To test the genetic role of glutamate receptors and theirCurrent models of schizophrenia and bipolar disorder implicate multiple genes, however their biological relationships remain elusive. To test the genetic role of glutamate receptors and their interacting scaffold proteins, the exons of ten glutamatergic 'hub' genes in 1304 individuals were re-sequenced in case and control samples. No significant difference in the overall number of non-synonymous single nucleotide polymorphisms (nsSNPs) was observed between cases and controls. However, cluster analysis of nsSNPs identified two exons encoding the cysteine-rich domain and first transmembrane helix of GRM1 as a risk locus with five mutations highly enriched within these domains. A new splice variant lacking the transmembrane GPCR domain of GRM1 was discovered in the human brain and the GRM1 mutation cluster could perturb the regulation of this variant. The predicted effect on individuals harbouring multiple mutations distributed in their ten hub genes was also examined. Diseased individuals possessed an increased load of deleteriousness from multiple concurrent rare and common coding variants. Together, these data suggest a disease model in which the interplay of compound genetic coding variants, distributed among glutamate receptors and their interacting proteins, contribute to the pathogenesis of schizophrenia and bipolar disorders.

• Association between ORMDL3, IL1RL1 and a deletion on chromosome 17q21 with asthma risk in Australia.

  Authors: Manuel A R Ferreira, Allan F McRae, Sarah E Medland, Dale R Nyholt, Scott D Gordon, Margaret J Wright, Anjali K Henders, Pamela A Madden, Peter M Visscher, Naomi R Wray, Andrew C Heath, Grant W Montgomery, David L Duffy, Nicholas G Martin

  European journal of human genetics : EJHG. 12/2010; 19(4):458-64.

  Genome-wide association studies followed by replication provide a powerful approach to map genetic risk factors for asthma. We sought to search for new variants associated with asthma and attempt toGenome-wide association studies followed by replication provide a powerful approach to map genetic risk factors for asthma. We sought to search for new variants associated with asthma and attempt to replicate the association with four loci reported previously (ORMDL3, PDE4D, DENND1B and IL1RL1). Genome-wide association analyses of individual single nucleotide polymorphisms (SNPs), rare copy number variants (CNVs) and overall CNV burden were carried out in 986 asthma cases and 1846 asthma-free controls from Australia. The most-associated locus in the SNP analysis was ORMDL3 (rs6503525, P = 4.8 × 10⁻⁷). Five other loci were associated with P < 10⁻⁵, most notably the chemokine CXC motif ligand 14 (CXCL14) gene (rs31263, P = 7.8 × 10⁻⁶). We found no evidence for association with the specific risk variants reported recently for PDE4D, DENND1B and ILR1L1. However, a variant in IL1RL1 that is in low linkage disequilibrium with that reported previously was associated with asthma risk after accounting for all variants tested (rs10197862, gene wide P = 0.01). This association replicated convincingly in an independent cohort (P = 2.4 × 10⁻⁴). A 300-kb deletion on chromosome 17q21 was associated with asthma risk, but this did not reach experiment-wide significance. Asthma cases and controls had comparable CNV rates, length and number of genes affected by deletions or duplications. In conclusion, we confirm the association between asthma risk and variants in ORMDL3 and identify a novel risk variant in IL1RL1. Follow-up of the 17q21 deletion in larger cohorts is warranted.

• A versatile gene-based test for genome-wide association studies.

  Authors: Jimmy Z Liu, Allan F McRae, Dale R Nyholt, Sarah E Medland, Naomi R Wray, Kevin M Brown, Nicholas K Hayward, Grant W Montgomery, Peter M Visscher, Nicholas G Martin, Stuart Macgregor

  American journal of human genetics. 07/2010; 87(1):139-45.

  We have derived a versatile gene-based test for genome-wide association studies (GWAS). Our approach, called VEGAS (versatile gene-based association study), is applicable to all GWAS designs,We have derived a versatile gene-based test for genome-wide association studies (GWAS). Our approach, called VEGAS (versatile gene-based association study), is applicable to all GWAS designs, including family-based GWAS, meta-analyses of GWAS on the basis of summary data, and DNA-pooling-based GWAS, where existing approaches based on permutation are not possible, as well as singleton data, where they are. The test incorporates information from a full set of markers (or a defined subset) within a gene and accounts for linkage disequilibrium between markers by using simulations from the multivariate normal distribution. We show that for an association study using singletons, our approach produces results equivalent to those obtained via permutation in a fraction of the computation time. We demonstrate proof-of-principle by using the gene-based test to replicate several genes known to be associated on the basis of results from a family-based GWAS for height in 11,536 individuals and a DNA-pooling-based GWAS for melanoma in approximately 1300 cases and controls. Our method has the potential to identify novel associated genes; provide a basis for selecting SNPs for replication; and be directly used in network (pathway) approaches that require per-gene association test statistics. We have implemented the approach in both an easy-to-use web interface, which only requires the uploading of markers with their association p-values, and a separate downloadable application.

• Genome-wide association study of height and body mass index in Australian twin families.

  Authors: Jimmy Z Liu, Sarah E Medland, Margaret J Wright, Anjali K Henders, Andrew C Heath, Pamela A F Madden, Alexis Duncan, Grant W Montgomery, Nicholas G Martin, Allan F McRae

  Twin research and human genetics : the official journal of the International Society for Twin Studies. 04/2010; 13(2):179-93.

  Human height and body mass index are influenced by a large number of genes, each with small effects, along with environment. To identify common genetic variants associated with these traits, weHuman height and body mass index are influenced by a large number of genes, each with small effects, along with environment. To identify common genetic variants associated with these traits, we performed genome-wide association studies in 11,536 individuals composed of Australian twins, family members, and unrelated individuals at approximately 550,000 genotyped SNPs. We identified a single genome-wide significant variant for height (P value=1.06x10(-9)) located in HHIP, a well-replicated height-associated gene. Suggestive levels of association were found for other known genes associated with height (P values<1x10(-6)): ADAMTSL3, EFEMP1, GPR126, and HMGA2; and BMI (P values<1x10(-4)): FTO and MC4R. Together, these variants explain less than 2% of total phenotypic variation for height and 0.5% for BMI.

• Congenital sensorineural deafness in Australian stumpy-tail cattle dogs is an autosomal recessive trait that maps to CFA10.

  Authors: Susan Sommerlad, Allan F McRae, Brenda McDonald, Isobel Johnstone, Leigh Cuttell, Jennifer M Seddon, Caroline A O'Leary

  PloS one. 01/2010; 5(10):e13364.

  Congenital sensorineural deafness is an inherited condition found in many dog breeds, including Australian Stumpy-tail Cattle Dogs (ASCD). This deafness is evident in young pups and may affect oneCongenital sensorineural deafness is an inherited condition found in many dog breeds, including Australian Stumpy-tail Cattle Dogs (ASCD). This deafness is evident in young pups and may affect one ear (unilateral) or both ears (bilateral). The genetic locus/loci involved is unknown for all dog breeds. The aims of this study were to determine incidence, inheritance mechanism, and possible association of congenital sensorineural deafness with coat colour in ASCD and to identify the genetic locus underpinning this disease. A total of 315 ASCD were tested for sensorineural deafness using the brain stem auditory evoked response (BAER) test. Disease penetrance was estimated directly, using the ratio of unilaterally to bilaterally deaf dogs, and segregation analysis was performed using Mendel. A complete genome screen was undertaken using 325 microsatellites spread throughout the genome, on a pedigree of 50 BAER tested ASCD in which deafness was segregating. Fifty-six dogs (17.8%) were deaf, with 17 bilaterally and 39 unilaterally deaf. Unilaterally deaf dogs showed no significant left/right bias (p = 0.19) and no significant difference was observed in frequencies between the sexes (p = 0.18). Penetrance of deafness was estimated as 0.72. Testing the association of red/blue coat colour and deafness without accounting for pedigree structure showed that red dogs were 1.8 times more likely to be deaf (p = 0.045). The within family association between red/blue coat colour and deafness was strongly significant (p = 0.00036), with red coat colour segregating more frequently with deafness (COR = 0.48). The relationship between deafness and coat speckling approached significance (p = 0.07), with the lack of statistical significance possibly due to only four families co-segregating for both deafness and speckling. The deafness phenotype was mapped to CFA10 (maximum linkage peak on CFA10 -log10 p-value = 3.64), as was both coat colour and speckling. Fine mapping was then performed on 45 of these 50 dogs and a further 48 dogs (n = 93). Sequencing candidate gene Sox10 in 6 hearing ASCD, 2 unilaterally deaf ASCD and 2 bilaterally deaf ASCD did not reveal any disease-associated mutations. Deafness in ASCD is an incompletely penetrant autosomal recessive inherited disease that maps to CFA10.

• Common Variants in the Trichohyalin Gene Are Associated with Straight Hair in Europeans.

  Authors: Sarah E Medland, Dale R Nyholt, Jodie N Painter, Brian P McEvoy, Allan F McRae, Gu Zhu, Scott D Gordon, Manuel A R Ferreira, Margaret J Wright, Anjali K Henders, Megan J Campbell, David L Duffy, Narelle K Hansell, Stuart Macgregor, Wendy S Slutske, Andrew C Heath, Grant W Montgomery, Nicholas G Martin

  American journal of human genetics. 11/2009;

  Hair morphology is highly differentiated between populations and among people of European ancestry. Whereas hair morphology in East Asian populations has been studied extensively, relatively littleHair morphology is highly differentiated between populations and among people of European ancestry. Whereas hair morphology in East Asian populations has been studied extensively, relatively little is known about the genetics of this trait in Europeans. We performed a genome-wide association scan for hair morphology (straight, wavy, curly) in three Australian samples of European descent. All three samples showed evidence of association implicating the Trichohyalin gene (TCHH), which is expressed in the developing inner root sheath of the hair follicle, and explaining approximately 6% of variance (p = 1.5 x 10(-31)). These variants are at their highest frequency in Northern Europeans, paralleling the distribution of the straight-hair EDAR variant in Asian populations.

• A Cytogenetic Abnormality and Rare Coding Variants Identify ABCA13 as a Candidate Gene in Schizophrenia, Bipolar Disorder, and Depression.

  Authors: Helen M Knight, Benjamin S Pickard, Alan Maclean, Mary P Malloy, Dinesh C Soares, Allan F McRae, Alison Condie, Angela White, William Hawkins, Kevin McGhee, Margaret Van Beck, Donald J Macintyre, John M Starr, Ian J Deary, Peter M Visscher, David J Porteous, Ronald E Cannon, David St Clair, Walter J Muir, Douglas H R Blackwood

  American journal of human genetics. 11/2009;

  Schizophrenia and bipolar disorder are leading causes of morbidity across all populations, with heritability estimates of approximately 80% indicating a substantial genetic component. PopulationSchizophrenia and bipolar disorder are leading causes of morbidity across all populations, with heritability estimates of approximately 80% indicating a substantial genetic component. Population genetics and genome-wide association studies suggest an overlap of genetic risk factors between these illnesses but it is unclear how this genetic component is divided between common gene polymorphisms, rare genomic copy number variants, and rare gene sequence mutations. We report evidence that the lipid transporter gene ABCA13 is a susceptibility factor for both schizophrenia and bipolar disorder. After the initial discovery of its disruption by a chromosome abnormality in a person with schizophrenia, we resequenced ABCA13 exons in 100 cases with schizophrenia and 100 controls. Multiple rare coding variants were identified including one nonsense and nine missense mutations and compound heterozygosity/homozygosity in six cases. Variants were genotyped in additional schizophrenia, bipolar, depression (n > 1600), and control (n > 950) cohorts and the frequency of all rare variants combined was greater than controls in schizophrenia (OR = 1.93, p = 0.0057) and bipolar disorder (OR = 2.71, p = 0.00007). The population attributable risk of these mutations was 2.2% for schizophrenia and 4.0% for bipolar disorder. In a study of 21 families of mutation carriers, we genotyped affected and unaffected relatives and found significant linkage (LOD = 4.3) of rare variants with a phenotype including schizophrenia, bipolar disorder, and major depression. These data identify a candidate gene, highlight the genetic overlap between schizophrenia, bipolar disorder, and depression, and suggest that rare coding variants may contribute significantly to risk of these disorders.

• Non-pathological paternal isodisomy of chromosome 2 detected from a genome-wide SNP scan.

  Authors: Matthew C Keller, Allan F McRae, Julie M McGaughran, Peter M Visscher, Nicholas G Martin, Grant W Montgomery

  American journal of medical genetics. Part A. 09/2009; 149A(8):1823-6.

• Geographical structure and differential natural selection amongst North European populations.

  Authors: Brian P McEvoy, Grant W Montgomery, Allan F McRae, Samuli Ripatti, Markus Perola, Tim D Spector, Lynn Cherkas, Kourosh R Ahmadi, Dorret Boomsma, Gonneke Willemsen [......] Aarno Palotie, Elisabeth Widen, Juha Muilu, Anne-Christine Syvanen, Ulrika Liljedahl, Orla Hardiman, Simon Cronin, Leena Peltonen, Nicholas G Martin, Peter M Visscher

  Genome research. 04/2009;

  Population structure can provide novel insight into the human past and recognizing and correcting for such stratification is a practical concern in gene mapping by many association methodologies. WePopulation structure can provide novel insight into the human past and recognizing and correcting for such stratification is a practical concern in gene mapping by many association methodologies. We investigate these patterns, primarily through principal component (PC) analysis of whole genome SNP polymorphism, in 2099 individuals from populations of Northern European origin (Ireland, UK, Netherlands, Denmark, Sweden, Finland, Australia and HapMap European-American). The major trends (PC1 and PC2) demonstrate an ability to detect geographic substructure, even over a small area like the British Isles, and this information can then be applied to finely dissect the ancestry of the European-Australian and -American samples. They simultaneously point to the importance of considering population stratification in what might be considered a small homogenous region. There is evidence from FST based analysis of genic and non-genic SNPs that differential positive selection has operated across these populations despite their short divergence time and relatively similar geographic and environmental range. The pressure appears to have been focused on genes involved in immunity, perhaps reflecting response to infectious disease epidemic. Such an event may explain a striking selective sweep centered on the rs2508049-G allele, close to HLA-G gene on chromosome 6. Evidence of the sweep extends over 8Mb/3.5cM region. Overall the results illustrate the power of dense genotype and sample data to explore regional population variation, the events that have crafted it and their implications in both explaining disease prevalence and mapping these genes by association.

• Family-based genome-wide association studies.

  Authors: Beben Benyamin, Peter M Visscher, Allan F McRae

  Pharmacogenomics. 03/2009; 10(2):181-190.

  In the last 2 years, the effort to identify genes affecting common diseases and complex traits has been accelerated through the use of genome-wide association studies (GWAS). The availability ofIn the last 2 years, the effort to identify genes affecting common diseases and complex traits has been accelerated through the use of genome-wide association studies (GWAS). The availability of existing large collections of linkage data paved the way for the use of family-based GWAS. Although most published GWAS used population-based designs, family-based designs have played an important role, particularly in replication stages. Family-based designs offer advantages in terms of quality control, the robustness to population stratification and the ability to perform genetic analyses that cannot be achieved using a sample of unrelated individuals, such as testing for the effect of imprinted genes on phenotypes, testing whether a genetic variant is inherited or de novo and combined linkage and association analysis.

• DNA methylation profiles in monozygotic and dizygotic twins.

  Authors: Zachary A Kaminsky, Thomas Tang, Sun-Chong Wang, Carolyn Ptak, Gabriel H T Oh, Albert H C Wong, Laura A Feldcamp, Carl Virtanen, Jonas Halfvarson, Curt Tysk, Allan F McRae, Peter M Visscher, Grant W Montgomery, Irving I Gottesman, Nicholas G Martin, Art Petronis

  Nature genetics. 02/2009;

  Twin studies have provided the basis for genetic and epidemiological studies in human complex traits. As epigenetic factors can contribute to phenotypic outcomes, we conducted a DNA methylationTwin studies have provided the basis for genetic and epidemiological studies in human complex traits. As epigenetic factors can contribute to phenotypic outcomes, we conducted a DNA methylation analysis in white blood cells (WBC), buccal epithelial cells and gut biopsies of 114 monozygotic (MZ) twins as well as WBC and buccal epithelial cells of 80 dizygotic (DZ) twins using 12K CpG island microarrays. Here we provide the first annotation of epigenetic metastability of approximately 6,000 unique genomic regions in MZ twins. An intraclass correlation (ICC)-based comparison of matched MZ and DZ twins showed significantly higher epigenetic difference in buccal cells of DZ co-twins (P = 1.2 x 10(-294)). Although such higher epigenetic discordance in DZ twins can result from DNA sequence differences, our in silico SNP analyses and animal studies favor the hypothesis that it is due to epigenomic differences in the zygotes, suggesting that molecular mechanisms of heritability may not be limited to DNA sequence differences.

• Variants in TF and HFE Explain approximately 40% of Genetic Variation in Serum-Transferrin Levels.

  Authors: Beben Benyamin, Allan F McRae, Gu Zhu, Scott Gordon, Anjali K Henders, Aarno Palotie, Leena Peltonen, Nicholas G Martin, Grant W Montgomery, John B Whitfield, Peter M Visscher

  American journal of human genetics. 01/2009;

  Only a small proportion of genetic variation in complex traits has been explained by SNPs from genome-wide association studies (GWASs). We report the results from two GWASs for serum markers of ironOnly a small proportion of genetic variation in complex traits has been explained by SNPs from genome-wide association studies (GWASs). We report the results from two GWASs for serum markers of iron status (serum iron, serum transferrin, transferrin saturation with iron, and serum ferritin), which are important in iron overload (e.g., hemochromatosis) and deficiency (e.g., anemia) conditions. We performed two GWASs on samples of Australians of European descent. In the first GWAS, 411 adolescent twins and their siblings were genotyped with 100K SNPs. rs1830084, 10.8 kb 3' of TF, was significantly associated with serum transferrin (p total association test = 1.0 x 10(-9); p within-family test = 2.2 x 10(-5)). In the second GWAS on an independent sample of 459 female monozygotic (MZ) twin pairs genotyped with 300K SNPs, we found rs3811647 (within intron 11 of TF, HapMap CEU r(2) with rs1830084 = 0.86) was significantly associated with serum transferrin (p = 3.0 x 10(-15)). In the second GWAS, we found two additional and independent SNPs on TF (rs1799852 and rs2280673) and confirmed the known C282Y mutation in HFE to be independently associated with serum transferrin. The three variants in TF (rs3811647, rs1799852 and rs2280673) plus the HFE C282Y mutation explained approximately 40% of genetic variation in serum transferrin (p = 7.8 x 10(-25)). These findings are potentially important for our understanding of iron metabolism and of regulation of hepatic protein secretion, and also strongly support the hypothesis that the genetic architecture of some endophenotypes may be simpler than that of disease.

• Divergence between Human Populations Estimated from Linkage Disequilibrium.

  Authors: John A Sved, Allan F McRae, Peter M Visscher

  American journal of human genetics. 12/2008;

  Observed linkage disequilibrium (LD) between genetic markers in different populations descended independently from a common ancestral population can be used to estimate their absolute time ofObserved linkage disequilibrium (LD) between genetic markers in different populations descended independently from a common ancestral population can be used to estimate their absolute time of divergence, because the correlation of LD between populations will be reduced each generation by an amount that, approximately, depends only on the recombination rate between markers. Although drift leads to divergence in allele frequencies, it has less effect on divergence in LD values. We derived the relationship between LD and time of divergence and verified it with coalescent simulations. We then used HapMap Phase II data to estimate time of divergence between human populations. Summed over large numbers of pairs of loci, we find a positive correlation of LD between African and non-African populations at levels of up to approximately 0.3 cM. We estimate that the observed correlation of LD is consistent with an effective separation time of approximately 1,000 generations or approximately 25,000 years before present. The most likely explanation for such relatively low separation times is the existence of substantial levels of migration between populations after the initial separation. Theory and results from coalescent simulations confirm that low levels of migration can lead to a downward bias in the estimate of separation time.

• The use of common mitochondrial variants to detect and characterise population structure in the Australian population: implications for genome-wide association studies.

  Authors: Enda M Byrne, Allan F McRae, Zhen Zhen Zhao, Nicholas G Martin, Grant W Montgomery, Peter M Visscher

  European journal of human genetics : EJHG. 08/2008;

  There is an increasing recognition of the potential role of variants in mitochondrial DNA and nuclear-encoded mitochondrial proteins in modifying disease risk. This has led to a rise in the number ofThere is an increasing recognition of the potential role of variants in mitochondrial DNA and nuclear-encoded mitochondrial proteins in modifying disease risk. This has led to a rise in the number of mitochondrial association studies being undertaken. The unique inheritance pattern of mitochondria makes mitochondrial DNA variation susceptible to having geographical structure. Such a structure may have a dramatic impact on mitochondrial association studies, particularly in heterogeneous populations. By combining self-reported ancestry data and mitochondrial genotype data for a sample of 3839 individuals from 1037 Australian families, population substructure is tested by looking for evidence of differences in mitochondrial haplogroup and single nucleotide polymorphism (SNP) frequencies between different ancestral groups in Australia. In addition, the substructure within ancestral groups is tested by comparing the similarity of mates to randomly drawn pairs of individuals from the same ancestral group. It is shown that there are significant differences in the frequency of variants both between European and non-European groups, and within Europe. This agrees with previous studies of European mitochondrial variation. No evidence was found for structure within ancestral groups. These results have implications for future association studies in the Australian population, and other populations of heterogeneous ancestry.European Journal of Human Genetics advance online publication, 9 July 2008; doi:10.1038/ejhg.2008.117.

• Power and SNP tagging in whole mitochondrial genome association studies.

  Authors: Allan F McRae, Enda M Byrne, Zhen Zhen Zhao, Grant W Montgomery, Peter M Visscher

  Genome research. 07/2008; 18(6):911-7.

  The application of genetic association studies to detect mitochondrial variants responsible for phenotypic variation has recently been demonstrated. However, the only power estimates currentlyThe application of genetic association studies to detect mitochondrial variants responsible for phenotypic variation has recently been demonstrated. However, the only power estimates currently available are based on the use of mitochondrial haplogroups, which can only tag a small fraction of the common variation in the mitochondrial genome. Here, power estimates are derived for a SNP-based study design for both disease (case-control) and quantitative trait mapping studies. Power is estimated using simulations based on a collection of publicly available mitochondrial sequences of European origin. The power when testing all common mitochondrial SNPs is shown to be equivalent to that when testing only tagging SNPs, despite the relatively high ratio of tagging SNPs to total SNPs resulting from the tagging of all SNPs with a minor allele frequency greater than 1%. The sample size requirements of mitochondrial genome association studies are compared with that of nuclear whole-genome studies. Remarkably, the trade off between the number of tests being performed and the proportion of phenotypic variance explained for a fixed effect size results in approximately equal sample sizes required for both study types, although the per individual cost for the mitochondrial association study is much less. To test the representation of the sequences used in the power simulations, a sample of 3839 individuals from 1037 Australian families was genotyped for 69 tagging SNPs. The strong concordance in allele frequencies and linkage disequilibrium between the European sequences and the Australian sample indicates that the results presented here are transferable across populations of European descent.