Anjali K Henders

Publications of Anjali K Henders

• Association of OPRD1 polymorphisms with heroin dependence in a large case-control series.

  Authors: Elliot C Nelson, Michael T Lynskey, Andrew C Heath, Naomi Wray, Arpana Agrawal, Fiona L Shand, Anjali K Henders, Leanne Wallace, Alexandre A Todorov, Andrew J Schrage, Pamela A F Madden, Louisa Degenhardt, Nicholas G Martin, Grant W Montgomery

  Addiction biology. 04/2012;

  Genes encoding the opioid receptors (OPRM1, OPRD1 and OPRK1) are obvious candidates for involvement in risk for heroin dependence. Prior association studies commonly had samples of modest size,Genes encoding the opioid receptors (OPRM1, OPRD1 and OPRK1) are obvious candidates for involvement in risk for heroin dependence. Prior association studies commonly had samples of modest size, included limited single nucleotide polymorphism (SNP) coverage of these genes and yielded inconsistent results. Participants for the current investigation included 1459 heroin-dependent cases ascertained from maintenance clinics in New South Wales, Australia, 1495 unrelated individuals selected from an Australian sample of twins and siblings as not meeting DSM-IV criteria for lifetime alcohol or illicit drug dependence (non-dependent controls) and 531 controls ascertained from economically disadvantaged neighborhoods in proximity to the maintenance clinics. A total of 136 OPRM1, OPRD1 and OPRK1 SNPs were genotyped in this sample. After controlling for admixture with principal components analysis, our comparison of cases to non-dependent controls found four OPRD1 SNPs in fairly high linkage disequilibrium for which adjusted P values remained significant (e.g. rs2236857; OR 1.25; P = 2.95 × 10(-4) ) replicating a previously reported association. A post hoc analysis revealed that the two SNP (rs2236857 and rs581111) GA haplotype in OPRD1 is associated with greater risk (OR 1.68; P = 1.41 × 10(-5) ). No OPRM1 or OPRK1 SNPs reached more than nominal significance. Comparisons of cases to neighborhood controls reached only nominal significance. Our results replicate a prior report providing strong evidence implicating OPRD1 SNPs and, in particular, the two SNP (rs2236857 and rs581111) GA haplotype in liability for heroin dependence. Support was not found for similar association involving either OPRM1 or OPRK1 SNPs.

• Cannabinoid Receptor Genotype Moderation of the Effects of Childhood Physical Abuse on Anhedonia and Depression.

  Authors: Arpana Agrawal, Elliot C Nelson, Andrew K Littlefield, Kathleen K Bucholz, Louisa Degenhardt, Anjali K Henders, Pamela A F Madden, Nicholas G Martin, Grant W Montgomery, Michele L Pergadia, Kenneth J Sher, Andrew C Heath, Michael T Lynskey

  Archives of general psychiatry. 03/2012;

  CONTEXT: The endocannabinoid system has been implicated in stress adaptation and the regulation of mood in rodent studies, but few human association studies have examined these links and replicationsCONTEXT: The endocannabinoid system has been implicated in stress adaptation and the regulation of mood in rodent studies, but few human association studies have examined these links and replications are limited. OBJECTIVES: To examine whether a synonymous polymorphism, rs1049353, in exon 4 of the gene encoding the human endocannabinoid receptor (CNR1) moderates the effect of self-reported childhood physical abuse on lifetime anhedonia and depression and to replicate this interaction in an independent sample. Design, Setting, and PARTICIPANTS: Genetic association study in 1041 young US women with replication in an independent Australian sample of 1428 heroin-dependent individuals as cases and 506 participants as neighborhood controls. MAIN OUTCOME MEASURES: Self-reported anhedonia and depression (with anhedonia). RESULTS: In both samples, individuals who experienced childhood physical abuse were considerably more likely to report lifetime anhedonia. However, in those with 1 or more copies of the minor allele of rs1049353, this pathogenic effect of childhood physical abuse was attenuated. Thus, in participants reporting childhood physical abuse, although 57.1% of those homozygous for the major allele reported anhedonia, only 28.6% of those who were carriers of the minor allele reported it (P = .01). The rs1049353 polymorphism also buffered the effects of childhood physical abuse on major depressive disorder; however, this influence was largely attributable to anhedonic depression. These effects were also noted in an independent sample, in which minor allele carriers were at decreased risk for anhedonia even when exposed to physical abuse. CONCLUSIONS: Consistent with preclinical findings, a synonymous CNR1 polymorphism, rs1049353, is linked to the effects of stress attributable to childhood physical abuse on anhedonia and anhedonic depression. This polymorphism reportedly resides in the neighborhood of an exon splice enhancer; hence, future studies should carefully examine its effect on expression and conformational variation in CNR1, particularly in relation to stress adaptation.

• Loci affecting gamma-glutamyl transferase in adults and adolescents show age × SNP interaction and cardiometabolic disease associations.

  Authors: Rita P Middelberg, Beben Benyamin, Marleen H M de Moor, Nicole M Warrington, Scott Gordon, Anjali K Henders, Sarah E Medland, Dale R Nyholt, Eco J C de Geus, Jouke J Hottenga [......] Lawrence J Beilin, Trevor A Mori, Margaret J Wright, Andrew C Heath, Pamela A F Madden, Dorret I Boomsma, Craig E Pennell, Grant W Montgomery, Nicholas G Martin, John B Whitfield

  Human molecular genetics. 01/2012; 21(2):446-55.

  Serum gamma-glutamyl transferase (GGT) activity is a marker of liver disease which is also prospectively associated with the risk of all-cause mortality, cardiovascular disease, type 2 diabetes andSerum gamma-glutamyl transferase (GGT) activity is a marker of liver disease which is also prospectively associated with the risk of all-cause mortality, cardiovascular disease, type 2 diabetes and cancers. We have discovered novel loci affecting GGT in a genome-wide association study (rs1497406 in an intergenic region of chromosome 1, P = 3.9 × 10(-8); rs944002 in C14orf73 on chromosome 14, P = 4.7 × 10(-13); rs340005 in RORA on chromosome 15, P = 2.4 × 10(-8)), and a highly significant heterogeneity between adult and adolescent results at the GGT1 locus on chromosome 22 (maximum P(HET) = 5.6 × 10(-12) at rs6519520). Pathway analysis of significant and suggestive single-nucleotide polymorphism associations showed significant overlap between genes affecting GGT and those affecting common metabolic and inflammatory diseases, and identified the hepatic nuclear factor (HNF) family as controllers of a network of genes affecting GGT. Our results reinforce the disease associations of GGT and demonstrate that control by the GGT1 locus varies with age.

• 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.

• Genome-wide association study identifies a new melanoma susceptibility locus at 1q21.3.

  Authors: Stuart Macgregor, Grant W Montgomery, Jimmy Z Liu, Zhen Zhen Zhao, Anjali K Henders, Mitchell Stark, Helen Schmid, Elizabeth A Holland, David L Duffy, Mingfeng Zhang [......] Graham G Giles, Bruce K Armstrong, Joanne F Aitken, Jiali Han, John L Hopper, Jeffrey M Trent, Kevin M Brown, Nicholas G Martin, Graham J Mann, Nicholas K Hayward

  Nature genetics. 11/2011; 43(11):1114-8.

  We performed a genome-wide association study of melanoma in a discovery cohort of 2,168 Australian individuals with melanoma and 4,387 control individuals. In this discovery phase, we confirm severalWe performed a genome-wide association study of melanoma in a discovery cohort of 2,168 Australian individuals with melanoma and 4,387 control individuals. In this discovery phase, we confirm several previously characterized melanoma-associated loci at MC1R, ASIP and MTAP-CDKN2A. We selected variants at nine loci for replication in three independent case-control studies (Europe: 2,804 subjects with melanoma, 7,618 control subjects; United States 1: 1,804 subjects with melanoma, 1,026 control subjects; United States 2: 585 subjects with melanoma, 6,500 control subjects). The combined meta-analysis of all case-control studies identified a new susceptibility locus at 1q21.3 (rs7412746, P = 9.0 × 10(-11), OR in combined replication cohorts of 0.89 (95% CI 0.85-0.95)). We also show evidence suggesting that melanoma associates with 1q42.12 (rs3219090, P = 9.3 × 10(-8)). The associated variants at the 1q21.3 locus span a region with ten genes, and plausible candidate genes for melanoma susceptibility include ARNT and SETDB1. Variants at the 1q21.3 locus do not seem to be associated with human pigmentation or measures of nevus density.

• 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.

• Association of polymorphisms in the hepatocyte growth factor gene promoter with keratoconus.

  Authors: Kathryn P Burdon, Stuart Macgregor, Yelena Bykhovskaya, Sharhbanou Javadiyan, Xiaohui Li, Kate J Laurie, Dorota Muszynska, Richard Lindsay, Judith Lechner, Talin Haritunians [......] Sudha K Iyengar, Kent D Taylor, Tony Phillips, Grant W Montgomery, Jerome I Rotter, Alex W Hewitt, Shiwani Sharma, Yaron S Rabinowitz, Colin Willoughby, Jamie E Craig

  Investigative ophthalmology & visual science. 10/2011; 52(11):8514-9.

  Keratoconus is a progressive disorder of the cornea that can lead to severe visual impairment or blindness. Although several genomic regions have been linked to rare familial forms of keratoconus, noKeratoconus is a progressive disorder of the cornea that can lead to severe visual impairment or blindness. Although several genomic regions have been linked to rare familial forms of keratoconus, no genes have yet been definitively identified for common forms of the disease. Two genome-wide association scans were undertaken in parallel. The first used pooled DNA from an Australian cohort, followed by typing of top-ranked single-nucleotide polymorphisms (SNPs) in individual DNA samples. The second was conducted in individually genotyped patients, and controls from the USA. Tag SNPs around the hepatocyte growth factor (HGF) gene were typed in three additional replication cohorts. Serum levels of HGF protein in normal individuals were assessed with ELISA and correlated with genotype. The only SNP observed to be associated in both the pooled discovery and primary replication cohort was rs1014091, located upstream of the HGF gene. The nearby SNP rs3735520 was found to be associated in the individually typed discovery cohort (P = 6.1 × 10(-7)). Genotyping of tag SNPs around HGF revealed association at rs3735520 and rs17501108/rs1014091 in four of the five cohorts. Meta-analysis of all five datasets together yielded suggestive P values for rs3735520 (P = 9.9 × 10(-7)) and rs17501108 (P = 9.9 × 10(-5)). In addition, SNP rs3735520 was found to be associated with serum HGF level in normal individuals (P = 0.036). Taken together, these results implicate genetic variation at the HGF locus with keratoconus susceptibility.

• Genetic variants in LPL, OASL and TOMM40/APOE-C1-C2-C4 genes are associated with multiple cardiovascular-related traits.

  Authors: Rita P S Middelberg, Manuel A R Ferreira, Anjali K Henders, Andrew C Heath, Pamela A F Madden, Grant W Montgomery, Nicholas G Martin, John B Whitfield

  BMC medical genetics. 09/2011; 12:123.

  Genome-wide association studies (GWAS) have become a major strategy for genetic dissection of human complex diseases. Analysing multiple phenotypes jointly may improve both our ability to detectGenome-wide association studies (GWAS) have become a major strategy for genetic dissection of human complex diseases. Analysing multiple phenotypes jointly may improve both our ability to detect genetic variants with multiple effects and our understanding of their common features. Allelic associations for multiple biochemical traits (serum alanine aminotransferase, aspartate aminotransferase, butrylycholinesterase (BCHE), C-reactive protein (CRP), ferritin, gamma glutamyltransferase (GGT), glucose, high-density lipoprotein cholesterol (HDL), insulin, low-density lipoprotein cholesterol (LDL), triglycerides and uric acid), and body-mass index, were examined. We aimed to identify common genetic variants affecting more than one of these traits using genome-wide association analysis in 2548 adolescents and 9145 adults from 4986 Australian twin families. Multivariate and univariate associations were performed. Multivariate analyses identified eight loci, and univariate association analyses confirmed two loci influencing more than one trait at p < 5 × 10-8. These are located on chromosome 8 (LPL gene affecting HDL and triglycerides) and chromosome 19 (TOMM40/APOE-C1-C2-C4 gene cluster affecting LDL and CRP). A locus on chromosome 12 (OASL gene) showed effects on GGT, LDL and CRP. The loci on chromosomes 12 and 19 unexpectedly affected LDL cholesterol and CRP in opposite directions. We identified three possible loci that may affect multiple traits and validated 17 previously-reported loci. Our study demonstrated the usefulness of examining multiple phenotypes jointly and highlights an anomalous effect on CRP, which is increasingly recognised as a marker of cardiovascular risk as well as of inflammation.

• GWAS of butyrylcholinesterase activity identifies four novel loci, independent effects within BCHE and secondary associations with metabolic risk factors.

  Authors: Beben Benyamin, Rita P Middelberg, Penelope A Lind, Anne M Valle, Scott Gordon, Dale R Nyholt, Sarah E Medland, Anjali K Henders, Andrew C Heath, Pamela A F Madden, Peter M Visscher, Daniel T O'Connor, Grant W Montgomery, Nicholas G Martin, John B Whitfield

  Human molecular genetics. 08/2011; 20(22):4504-14.

  Serum butyrylcholinesterase (BCHE) activity is associated with obesity, blood pressure and biomarkers of cardiovascular and diabetes risk. We have conducted a genome-wide association scan to discoverSerum butyrylcholinesterase (BCHE) activity is associated with obesity, blood pressure and biomarkers of cardiovascular and diabetes risk. We have conducted a genome-wide association scan to discover genetic variants affecting BCHE activity, and to clarify whether the associations between BCHE activity and cardiometabolic risk factors are caused by variation in BCHE or whether BCHE variation is secondary to the metabolic abnormalities. We measured serum BCHE in adolescents and adults from three cohorts of Australian twin and family studies. The genotypes from ∼2.4 million single-nucleotide polymorphisms (SNPs) were available in 8791 participants with BCHE measurements. We detected significant associations with BCHE activity at three independent groups of SNPs at the BCHE locus (P = 5.8 × 10(-262), 7.8 × 10(-47), 2.9 × 10(-12)) and at four other loci: RNPEP (P = 9.4 × 10(-16)), RAPH1-ABI2 (P = 4.1 × 10(-18)), UGT1A1 (P = 4.0 × 10(-8)) and an intergenic region on chromosome 8 (P = 1.4 × 10(-8)). These loci affecting BCHE activity were not associated with metabolic risk factors. On the other hand, SNPs in genes previously associated with metabolic risk had effects on BCHE activity more often than can be explained by chance. In particular, SNPs within FTO and GCKR were associated with BCHE activity, but their effects were partly mediated by body mass index and triglycerides, respectively. We conclude that variation in BCHE activity is due to multiple variants across the spectrum from uncommon/large effect to common/small effect, and partly results from (rather than causes) metabolic abnormalities.

• High-density fine-mapping of a chromosome 10q26 linkage peak suggests association between endometriosis and variants close to CYP2C19.

  Authors: Jodie N Painter, Dale R Nyholt, Andrew Morris, Zhen Z Zhao, Anjali K Henders, Ann Lambert, Leanne Wallace, Nicholas G Martin, Stephen H Kennedy, Susan A Treloar, Krina T Zondervan, Grant W Montgomery

  Fertility and sterility. 06/2011; 95(7):2236-40.

  To refine a previously reported linkage peak for endometriosis on chromosome 10q26, and conduct follow-up analyses and a fine-mapping association study across the region to identify new candidateTo refine a previously reported linkage peak for endometriosis on chromosome 10q26, and conduct follow-up analyses and a fine-mapping association study across the region to identify new candidate genes for endometriosis. Case-control study. Academic research. Cases=3,223 women with surgically confirmed endometriosis; controls=1,190 women without endometriosis and 7,060 population samples. Analysis of 11,984 single nucleotide polymorphisms on chromosome 10. Allele frequency differences between cases and controls. Linkage analyses on families grouped by endometriosis symptoms (primarily subfertility) provided increased evidence for linkage (logarithm of odds score=3.62) near a previously reported linkage peak. Three independent association signals were found at 96.59 Mb (rs11592737), 105.63 Mb (rs1253130), and 124.25 Mb (rs2250804). Analyses including only samples from linkage families supported the association at all three regions. However, only rs11592737 in the cytochrome P450 subfamily C (CYP2C19) gene was replicated in an independent sample of 2,079 cases and 7,060 population controls. The role of the CYP2C19 gene in conferring risk for endometriosis warrants further investigation.

• Genome-wide association study identifies susceptibility loci for open angle glaucoma at TMCO1 and CDKN2B-AS1.

  Authors: Kathryn P Burdon, Stuart Macgregor, Alex W Hewitt, Shiwani Sharma, Glyn Chidlow, Richard A Mills, Patrick Danoy, Robert Casson, Ananth C Viswanathan, Jimmy Z Liu [......] Paul Leo, Jie Jin Wang, Elena Rochtchina, Dale R Nyholt, Nicholas G Martin, Grant W Montgomery, Paul Mitchell, Matthew A Brown, David A Mackey, Jamie E Craig

  Nature genetics. 06/2011; 43(6):574-8.

  We report a genome-wide association study for open-angle glaucoma (OAG) blindness using a discovery cohort of 590 individuals with severe visual field loss (cases) and 3,956 controls. We identifiedWe report a genome-wide association study for open-angle glaucoma (OAG) blindness using a discovery cohort of 590 individuals with severe visual field loss (cases) and 3,956 controls. We identified associated loci at TMCO1 (rs4656461[G] odds ratio (OR) = 1.68, P = 6.1 × 10(-10)) and CDKN2B-AS1 (rs4977756[A] OR = 1.50, P = 4.7 × 10(-9)). We replicated these associations in an independent cohort of cases with advanced OAG (rs4656461 P = 0.010; rs4977756 P = 0.042) and two additional cohorts of less severe OAG (rs4656461 combined discovery and replication P = 6.00 × 10(-14), OR = 1.51, 95% CI 1.35-1.68; rs4977756 combined P = 1.35 × 10(-14), OR = 1.39, 95% CI 1.28-1.51). We show retinal expression of genes at both loci in human ocular tissues. We also show that CDKN2A and CDKN2B are upregulated in the retina of a rat model of glaucoma.

• LPAR1 and ITGA4 regulate peripheral blood monocyte counts.

  Authors: Narelle Maugeri, Joseph E Powell, Peter A C 't Hoen, Eco J C de Geus, Gonneke Willemsen, Mathijs Kattenberg, Anjali K Henders, Leanne Wallace, Brenda Penninx, Jouke-Jan Hottenga, Sarah E Medland, Viatcheslav Saviouk, Nicholas G Martin, Peter M Visscher, Gert-Jan B van Ommen, Ian H Frazer, Dorret I Boomsma, Grant W Montgomery, Manuel A R Ferreira

  Human mutation. 05/2011; 32(8):873-6.

  We recently mapped a quantitative trait locus for monocyte counts to chromosome 9q31 (rs7023923). Here we extend this work by showing with two independent approaches that rs7023923 regulates theWe recently mapped a quantitative trait locus for monocyte counts to chromosome 9q31 (rs7023923). Here we extend this work by showing with two independent approaches that rs7023923 regulates the expression levels of the nearby LPAR1 gene (P<0.0001), specifically implicating this gene in monocyte development. Furthermore, we tested 10 additional loci identified in the original analysis for replication in 1,122 individuals and confirm that rs6740847 near the alpha-4-integrin gene (ITGA4) associates with variation in monocyte counts (combined P=2.7×10(-10)). This variant is in complete linkage disequilibrium (r(2) =1) with a previously reported eQTL for ITGA4 (rs2124440), indicating that this is the likely causal gene in the region. Our results indicate that rs7023923 and rs6740847 respectively upregulate LPAR1 and downregulate ITGA4 expression and this increases the number of monocytes circulating in the peripheral blood. Further studies that investigate the downstream mechanism involved and the impact on immune function are warranted.

• A 3p26-3p25 genetic linkage finding for DSM-IV major depression in heavy smoking families.

  Authors: Michele L Pergadia, Anne L Glowinski, Naomi R Wray, Arpana Agrawal, Scott F Saccone, Anu Loukola, Ulla Broms, Tellervo Korhonen, Brenda W J H Penninx, Julia D Grant [......] Gonneke Willemsen, Sarah E Medland, Dorret I Boomsma, Grant W Montgomery, John P Rice, Alison M Goate, Andrew C Heath, Jaakko Kaprio, Nicholas G Martin, Pamela A F Madden

  The American journal of psychiatry. 05/2011; 168(8):848-52.

  The authors tested for genetic linkage of DSM-IV-diagnosed major depressive disorder in families that were ascertained for cigarette smoking. Within a study that targeted families characterized by aThe authors tested for genetic linkage of DSM-IV-diagnosed major depressive disorder in families that were ascertained for cigarette smoking. Within a study that targeted families characterized by a history of smoking, analyses derived a subset of 91 Australian families with two or more offspring with a history of DSM-IV major depressive disorder (affected sibling pairs, N=187) and 25 Finnish families (affected sibling pairs, N=33). Within this affected sibling pairs design, the authors conducted nonparametric linkage analysis. In the Australian heavy smoking families, the authors found a genome-wide significant multipoint LOD score of 4.14 for major depressive disorder on chromosome 3 at 24.9 cM (3p26-3p25). Genome-wide significant linkage was detected for major depressive disorder on chromosome 3p in a sample ascertained for smoking. A linkage peak at this location was also observed in an independent study of major depressive disorder.

• A quantitative-trait genome-wide association study of alcoholism risk in the community: findings and implications.

  Authors: Andrew C Heath, John B Whitfield, Nicholas G Martin, Michele L Pergadia, Alison M Goate, Penelope A Lind, Brian P McEvoy, Andrew J Schrage, Julia D Grant, Yi-Ling Chou, Rachel Zhu, Anjali K Henders, Sarah E Medland, Scott D Gordon, Elliot C Nelson, Arpana Agrawal, Dale R Nyholt, Kathleen K Bucholz, Pamela A F Madden, Grant W Montgomery

  Biological psychiatry. 04/2011; 70(6):513-8.

  Given moderately strong genetic contributions to variation in alcoholism and heaviness of drinking (50% to 60% heritability) with high correlation of genetic influences, we have conducted aGiven moderately strong genetic contributions to variation in alcoholism and heaviness of drinking (50% to 60% heritability) with high correlation of genetic influences, we have conducted a quantitative trait genome-wide association study (GWAS) for phenotypes related to alcohol use and dependence. Diagnostic interview and blood/buccal samples were obtained from sibships ascertained through the Australian Twin Registry. Genome-wide single nucleotide polymorphism (SNP) genotyping was performed with 8754 individuals (2062 alcohol-dependent cases) selected for informativeness for alcohol use disorder and associated quantitative traits. Family-based association tests were performed for alcohol dependence, dependence factor score, and heaviness of drinking factor score, with confirmatory case-population control comparisons using an unassessed population control series of 3393 Australians with genome-wide SNP data. No findings reached genome-wide significance (p = 8.4 × 10(-8) for this study), with lowest p value for primary phenotypes of 1.2 × 10(-7). Convergent findings for quantitative consumption and diagnostic and quantitative dependence measures suggest possible roles for a transmembrane protein gene (TMEM108) and for ANKS1A. The major finding, however, was small effect sizes estimated for individual SNPs, suggesting that hundreds of genetic variants make modest contributions (1/4% of variance or less) to alcohol dependence risk. We conclude that 1) meta-analyses of consumption data may contribute usefully to gene discovery; 2) translation of human alcoholism GWAS results to drug discovery or clinically useful prediction of risk will be challenging; and 3) through accumulation across studies, GWAS data may become valuable for improved genetic risk differentiation in research in biological psychiatry (e.g., prospective high-risk or resilience studies).

• Genome-wide association study identifies a locus at 7p15.2 associated with endometriosis.

  Authors: Jodie N Painter, Carl A Anderson, Dale R Nyholt, Stuart Macgregor, Jianghai Lin, Sang Hong Lee, Ann Lambert, Zhen Z Zhao, Fenella Roseman, Qun Guo [......] Anjali K Henders, Peter M Visscher, Peter Kraft, Nicholas G Martin, Andrew P Morris, Susan A Treloar, Stephen H Kennedy, Stacey A Missmer, Grant W Montgomery, Krina T Zondervan

  Nature genetics. 01/2011; 43(1):51-4.

  Endometriosis is a common gynecological disease associated with pelvic pain and subfertility. We conducted a genome-wide association study (GWAS) in 3,194 individuals with surgically confirmedEndometriosis is a common gynecological disease associated with pelvic pain and subfertility. We conducted a genome-wide association study (GWAS) in 3,194 individuals with surgically confirmed endometriosis (cases) and 7,060 controls from Australia and the UK. Polygenic predictive modeling showed significantly increased genetic loading among 1,364 cases with moderate to severe endometriosis. The strongest association signal was on 7p15.2 (rs12700667) for 'all' endometriosis (P = 2.6 × 10⁻⁷, odds ratio (OR) = 1.22, 95% CI 1.13-1.32) and for moderate to severe disease (P = 1.5 × 10⁻⁹, OR = 1.38, 95% CI 1.24-1.53). We replicated rs12700667 in an independent cohort from the United States of 2,392 self-reported, surgically confirmed endometriosis cases and 2,271 controls (P = 1.2 × 10⁻³, OR = 1.17, 95% CI 1.06-1.28), resulting in a genome-wide significant P value of 1.4 × 10⁻⁹ (OR = 1.20, 95% CI 1.13-1.27) for 'all' endometriosis in our combined datasets of 5,586 cases and 9,331 controls. rs12700667 is located in an intergenic region upstream of the plausible candidate genes NFE2L3 and HOXA10.

• Impact of the genome on the epigenome is manifested in DNA methylation patterns of imprinted regions in monozygotic and dizygotic twins.

  Authors: Marcel W Coolen, Aaron L Statham, Wenjia Qu, Megan J Campbell, Anjali K Henders, Grant W Montgomery, Nick G Martin, Susan J Clark

  PloS one. 01/2011; 6(10):e25590.

  One of the best studied read-outs of epigenetic change is the differential expression of imprinted genes, controlled by differential methylation of imprinted control regions (ICRs). To address theOne of the best studied read-outs of epigenetic change is the differential expression of imprinted genes, controlled by differential methylation of imprinted control regions (ICRs). To address the impact of genotype on the epigenome, we performed a detailed study in 128 pairs of monozygotic (MZ) and 128 pairs of dizygotic (DZ) twins, interrogating the DNA methylation status of the ICRs of IGF2, H19, KCNQ1, GNAS and the non-imprinted gene RUNX1. While we found a similar overall pattern of methylation between MZ and DZ twins, we also observed a high degree of variability in individual CpG methylation levels, notably at the H19/IGF2 loci. A degree of methylation plasticity independent of the genome sequence was observed, with both local and regional CpG methylation changes, discordant between MZ and DZ individual pairs. However, concordant gains or losses of methylation, within individual twin pairs were more common in MZ than DZ twin pairs, indicating that de novo and/or maintenance methylation is influenced by the underlying DNA sequence. Specifically, for the first time we showed that the rs10732516 [A] polymorphism, located in a critical CTCF binding site in the H19 ICR locus, is strongly associated with increased hypermethylation of specific CpG sites in the maternal H19 allele. Together, our results highlight the impact of the genome on the epigenome and demonstrate that while DNA methylation states are tightly maintained between genetically identical and related individuals, there remains considerable epigenetic variation that may contribute to disease susceptibility.

• A simple and fast two-locus quality control test to detect false positives due to batch effects in genome-wide association studies.

  Authors: Sang Hong Lee, Dale R Nyholt, Stuart Macgregor, Anjali K Henders, Krina T Zondervan, Grant W Montgomery, Peter M Visscher

  Genetic epidemiology. 12/2010; 34(8):854-62.

  The impact of erroneous genotypes having passed standard quality control (QC) can be severe in genome-wide association studies, genotype imputation, and estimation of heritability and prediction ofThe impact of erroneous genotypes having passed standard quality control (QC) can be severe in genome-wide association studies, genotype imputation, and estimation of heritability and prediction of genetic risk based on single nucleotide polymorphisms (SNP). To detect such genotyping errors, a simple two-locus QC method, based on the difference in test statistic of association between single SNPs and pairs of SNPs, was developed and applied. The proposed approach could detect many problematic SNPs with statistical significance even when standard single SNP QC analyses fail to detect them in real data. Depending on the data set used, the number of erroneous SNPs that were not filtered out by standard single SNP QC but detected by the proposed approach varied from a few hundred to thousands. Using simulated data, it was shown that the proposed method was powerful and performed better than other tested existing methods. The power of the proposed approach to detect erroneous genotypes was ∼80% for a 3% error rate per SNP. This novel QC approach is easy to implement and computationally efficient, and can lead to a better quality of genotypes for subsequent genotype-phenotype investigations.

• 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.