Nicholas G Martin

Publications of Nicholas G Martin

• Association Between In Vivo Alcohol Metabolism and Genetic Variation in Pathways that Metabolize the Carbon Skeleton of Ethanol and NADH Reoxidation in the Alcohol Challenge Twin Study.

  Authors: Penelope A Lind, Stuart Macgregor, Andrew C Heath, Pamela A F Madden, Grant W Montgomery, Nicholas G Martin, John B Whitfield

  Alcoholism, clinical and experimental research. 05/2012;

  BACKGROUND: Variation in alcohol metabolism affects the duration of intoxication and alcohol use. While the majority of genetic association studies investigating variation in alcohol metabolism haveBACKGROUND: Variation in alcohol metabolism affects the duration of intoxication and alcohol use. While the majority of genetic association studies investigating variation in alcohol metabolism have focused on polymorphisms in alcohol or aldehyde dehydrogenases, we have now tested for association with genes in alternative metabolic pathways that catalyze the carbon skeleton of ethanol (EtOH) and NADH reoxidation. METHODS: Nine hundred fifty single nucleotide polymorphisms (SNPs) spanning 14 genes (ACN9, ACSS1, ACSS2, ALDH1A1, CAT, CYP2E1, GOT1, GOT2, MDH1, MDH2, SLC25A10, SLC25A11, SLC25A12, SLC25A13) were genotyped in 352 young adults who participated in an alcohol challenge study. Traits tested were blood alcohol concentration (BAC), breath alcohol concentration (BrAC), peak alcohol concentration, and rates of alcohol absorption and elimination. Allelic association was tested using quantitative univariate and multivariate methods. RESULTS: A CYP2E1 promoter SNP (rs4838767, minor allele frequency 0.008) exceeded the threshold for study-wide significance (4.01 × 10(-5) ) for 2 early BAC, 8 BrAC measures, and the peak BrAC. For each phenotype, the minor C allele was related to a lower alcohol concentration, most strongly for the fourth BrAC (p = 2.07 × 10(-7) ) explaining ~8% of the phenotypic variance. We also observed suggestive patterns of association with variants in ALDH1A1 and on chromosome 17 near SLC25A11 for aspects of blood and breath alcohol metabolism. An SNP upstream of GOT1 (rs2490286) reached study-wide significance for multivariate BAC metabolism (p = 0.000040). CONCLUSIONS: Overall, we did not find strong evidence that variation in genes coding for proteins that further metabolize the carbon backbone of acetaldehyde, or contribute to mechanisms for regenerating NAD from NADH, affects alcohol metabolism in our European-descent subjects. However, based on the breath alcohol data, variation in the promoter of CYP2E1 may play a role in preabsorptive or early hepatic alcohol metabolism, but more samples are required to validate this finding.

• Genetic and Environmental Influences on Analogical and Categorical Verbal and Spatial Reasoning in 12-Year Old Twins.

  Authors: Miriam A Mosing, Jane Mellanby, Nicholas G Martin, Margaret J Wright

  Behavior genetics. 05/2012;

  Research on the genetic influences on different abstract reasoning skills (fluid intelligence) and their interrelation (especially in childhood/adolescence) has been sparse. A novel cognitive testResearch on the genetic influences on different abstract reasoning skills (fluid intelligence) and their interrelation (especially in childhood/adolescence) has been sparse. A novel cognitive test battery, the Verbal and Spatial Reasoning test for Children (VESPARCH 1), consisting of four matched (in terms of test-procedure and design) subtests assessing verbal [analogical (VA) and categorical (VC)] and spatial [analogical (SA) and categorical (SC)] reasoning, was administered to a population based sample of 12-year old twins (169 pairs). Multivariate analysis was conducted to explore the genetic relationship between the four cognitive sub-domains. Heritabilities were 0.62 (VA), 0.49 (VC), 0.52 (SA), and 0.20 (SC). Genetic influences were due to one common factor with no specific genetic influences. This shared genetic factor also explained almost the entire covariance between the domains, as environmental variance was largely specific to each subtest. The finding of no genetic influences specific to each subtest may be due to the uniquely matched design of the VESPARCH 1, reducing confoundment of different test modalities used in conventional tests. For future research or when interpreting previous studies, our findings highlight the importance of taking such potential artefacts (i.e. different test modalities for different sub-domains) into account when exploring the relationship between cognitive sub-domains.

• Relationship of a Variant in the NTRK1 Gene to White Matter Microstructure in Young Adults.

  Authors: Meredith N Braskie, Neda Jahanshad, Jason L Stein, Marina Barysheva, Kori Johnson, Katie L McMahon, Greig I de Zubicaray, Nicholas G Martin, Margaret J Wright, John M Ringman, Arthur W Toga, Paul M Thompson

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 04/2012; 32(17):5964-5972.

  The NTRK1 gene (also known as TRKA) encodes a high-affinity receptor for NGF, a neurotrophin involved in nervous system development and myelination. NTRK1 has been implicated in neurological functionThe NTRK1 gene (also known as TRKA) encodes a high-affinity receptor for NGF, a neurotrophin involved in nervous system development and myelination. NTRK1 has been implicated in neurological function via links between the T allele at rs6336 (NTRK1-T) and schizophrenia risk. A variant in the neurotrophin gene, BDNF, was previously associated with white matter integrity in young adults, highlighting the importance of neurotrophins to white matter development. We hypothesized that NTRK1-T would relate to lower fractional anisotropy in healthy adults. We scanned 391 healthy adult human twins and their siblings (mean age: 23.6 ± 2.2 years; 31 NTRK1-T carriers, 360 non-carriers) using 105-gradient diffusion tensor imaging at 4 tesla. We evaluated in brain white matter how NTRK1-T and NTRK1 rs4661063 allele A (rs4661063-A, which is in moderate linkage disequilibrium with rs6336) related to voxelwise fractional anisotropy-a common diffusion tensor imaging measure of white matter microstructure. We used mixed-model regression to control for family relatedness, age, and sex. The sample was split in half to test reproducibility of results. The false discovery rate method corrected for voxelwise multiple comparisons. NTRK1-T and rs4661063-A correlated with lower white matter fractional anisotropy, independent of age and sex (multiple-comparisons corrected: false discovery rate critical p = 0.038 for NTRK1-T and 0.013 for rs4661063-A). In each half-sample, the NTRK1-T effect was replicated in the cingulum, corpus callosum, superior and inferior longitudinal fasciculi, inferior fronto-occipital fasciculus, superior corona radiata, and uncinate fasciculus. Our results suggest that NTRK1-T is important for developing white matter microstructure.

• Predicting White Matter Integrity from Multiple Common Genetic Variants.

  Authors: Omid Kohannim, Neda Jahanshad, Meredith N Braskie, Jason L Stein, Ming-Chang Chiang, April H Reese, Derrek P Hibar, Arthur W Toga, Katie L McMahon, Greig I de Zubicaray, Sarah E Medland, Grant W Montgomery, Nicholas G Martin, Margaret J Wright, Paul M Thompson

  Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 04/2012;

  Several common genetic variants have recently been discovered that appear to influence white matter microstructure, as measured by diffusion tensor imaging (DTI). Each genetic variant explains only aSeveral common genetic variants have recently been discovered that appear to influence white matter microstructure, as measured by diffusion tensor imaging (DTI). Each genetic variant explains only a small proportion of the variance in brain microstructure, so we set out to explore their combined effect on the white matter integrity of the corpus callosum. We measured six common candidate single-nucleotide polymorphisms (SNPs) in the COMT, NTRK1, BDNF, ErbB4, CLU, and HFE genes, and investigated their individual and aggregate effects on white matter structure in 395 healthy adult twins and siblings (age: 20-30 years). All subjects were scanned with 4-tesla 94-direction high angular resolution diffusion imaging. When combined using mixed-effects linear regression, a joint model based on five of the candidate SNPs (COMT, NTRK1, ErbB4, CLU, and HFE) explained ∼6% of the variance in the average fractional anisotropy (FA) of the corpus callosum. This predictive model had detectable effects on FA at 82% of the corpus callosum voxels, including the genu, body, and splenium. Predicting the brain's fiber microstructure from genotypes may ultimately help in early risk assessment, and eventually, in personalized treatment for neuropsychiatric disorders in which brain integrity and connectivity are affected.Neuropsychopharmacology advance online publication, 18 April 2012; doi:10.1038/npp.2012.49.

• Identification of common variants associated with human hippocampal and intracranial volumes.

  Authors: Jason L Stein, Sarah E Medland, Alejandro Arias Vasquez, Derrek P Hibar, Rudy E Senstad, Anderson M Winkler, Roberto Toro, Katja Appel, Richard Bartecek, Orjan Bergmann [......] Philipp G Sämann, Andrew J Saykin, Gunter Schumann, Jordan W Smoller, Joanna M Wardlaw, Michael E Weale, Nicholas G Martin, Barbara Franke, Margaret J Wright, Paul M Thompson

  Nature genetics. 04/2012;

  Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker ofIdentifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer's disease and is reduced in schizophrenia, major depression and mesial temporal lobe epilepsy. Whereas many brain imaging phenotypes are highly heritable, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10(-16)) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10(-12)). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10(-7)).

• Common variants at 12q14 and 12q24 are associated with hippocampal volume.

  Authors: Joshua C Bis, Charles Decarli, Albert Vernon Smith, Fedde van der Lijn, Fabrice Crivello, Myriam Fornage, Stephanie Debette, Joshua M Shulman, Helena Schmidt, Velandai Srikanth [......] W T Longstreth, Matthew A Brown, David A Bennett, Cornelia M van Duijn, Thomas H Mosley, Reinhold Schmidt, Christophe Tzourio, Lenore J Launer, M Arfan Ikram, Sudha Seshadri

  Nature genetics. 04/2012;

  Aging is associated with reductions in hippocampal volume that are accelerated by Alzheimer's disease and vascular risk factors. Our genome-wide association study (GWAS) of dementia-free persons (n =Aging is associated with reductions in hippocampal volume that are accelerated by Alzheimer's disease and vascular risk factors. Our genome-wide association study (GWAS) of dementia-free persons (n = 9,232) identified 46 SNPs at four loci with P values of <4.0 × 10(-7). In two additional samples (n = 2,318), associations were replicated at 12q14 within MSRB3-WIF1 (discovery and replication; rs17178006; P = 5.3 × 10(-11)) and at 12q24 near HRK-FBXW8 (rs7294919; P = 2.9 × 10(-11)). Remaining associations included one SNP at 2q24 within DPP4 (rs6741949; P = 2.9 × 10(-7)) and nine SNPs at 9p33 within ASTN2 (rs7852872; P = 1.0 × 10(-7)); along with the chromosome 12 associations, these loci were also associated with hippocampal volume (P < 0.05) in a third younger, more heterogeneous sample (n = 7,794). The SNP in ASTN2 also showed suggestive association with decline in cognition in a largely independent sample (n = 1,563). These associations implicate genes related to apoptosis (HRK), development (WIF1), oxidative stress (MSR3B), ubiquitination (FBXW8) and neuronal migration (ASTN2), as well as enzymes targeted by new diabetes medications (DPP4), indicating new genetic influences on hippocampal size and possibly the risk of cognitive decline and dementia.

• 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.

• Meta-analyses of genome-wide linkage scans of anxiety-related phenotypes.

  Authors: Bradley T Webb, An-Yuan Guo, Brion S Maher, Zhongming Zhao, Edwin J van den Oord, Kenneth S Kendler, Brien P Riley, Nathan A Gillespie, Carol A Prescott, Christel M Middeldorp [......] Abby J Fyer, Patricia Huezo-Diaz, Peter McGuffin, Anne Farmer, Ian W Craig, Cathryn Lewis, Pak Sham, Raymond R Crowe, Jonathan Flint, John M Hettema

  European journal of human genetics : EJHG. 04/2012;

  Genetic factors underlying trait neuroticism, reflecting a tendency towards negative affective states, may overlap genetic susceptibility for anxiety disorders and help explain the extensiveGenetic factors underlying trait neuroticism, reflecting a tendency towards negative affective states, may overlap genetic susceptibility for anxiety disorders and help explain the extensive comorbidity amongst internalizing disorders. Genome-wide linkage (GWL) data from several studies of neuroticism and anxiety disorders have been published, providing an opportunity to test such hypotheses and identify genomic regions that harbor genes common to these phenotypes. In all, 11 independent GWL studies of either neuroticism (n=8) or anxiety disorders (n=3) were collected, which comprised of 5341 families with 15 529 individuals. The rank-based genome scan meta-analysis (GSMA) approach was used to analyze each trait separately and combined, and global correlations between results were examined. False discovery rate (FDR) analysis was performed to test for enrichment of significant effects. Using 10 cM intervals, bins nominally significant for both GSMA statistics, P(SR) and P(OR), were found on chromosomes 9, 11, 12, and 14 for neuroticism and on chromosomes 1, 5, 15, and 16 for anxiety disorders. Genome-wide, the results for the two phenotypes were significantly correlated, and a combined analysis identified additional nominally significant bins. Although none reached genome-wide significance, an excess of significant P(SR)P-values were observed, with 12 bins falling under a FDR threshold of 0.50. As demonstrated by our identification of multiple, consistent signals across the genome, meta-analytically combining existing GWL data is a valuable approach to narrowing down regions relevant for anxiety-related phenotypes. This may prove useful for prioritizing emerging genome-wide association data for anxiety disorders.European Journal of Human Genetics advance online publication, 4 April 2012; doi:10.1038/ejhg.2012.47.

• Use of a Predictive Model Derived from In Vivo Endophenotype Measurements to Demonstrate Associations with a Complex Locus, CYP2A6.

  Authors: A Joseph Bloom, Oscar Harari, Maribel Martinez, Pamela A F Madden, Nicholas G Martin, Grant W Montgomery, John P Rice, Sharon E Murphy, Laura J Bierut, Alison Goate

  Human molecular genetics. 03/2012;

  This study demonstrates a novel approach to test associations between highly heterogeneous genetic loci and complex phenotypes. Previous investigations of the relationship between Cytochrome P450 2A6This study demonstrates a novel approach to test associations between highly heterogeneous genetic loci and complex phenotypes. Previous investigations of the relationship between Cytochrome P450 2A6 (CYP2A6) genotype and smoking phenotypes made comparisons by dividing subjects into broad categories based on assumptions that simplify the range of function of different CYP2A6 alleles, their numerous possible diplotype combinations, and non-additive allele effects. A predictive model that translates CYP2A6 diplotype into a single continuous variable was previously derived from an in vivo metabolism experiment in 189 European Americans. Here we apply this model to assess associations between genotype, inferred nicotine metabolism, and smoking behaviors in larger samples without direct nicotine metabolism measurements. CYP2A6 genotype is not associated with nicotine dependence, as defined by the Fagerström Test of Nicotine Dependence (FTND), demonstrating that cigarettes smoked per day (CPD) and nicotine dependence have distinct genetic correlates. The predicted metric is significantly associated with CPD among African Americans and European American dependent smokers. Individual slow metabolizing genotypes are associated with lower CPD, but the predicted metric is the best predictor of CPD. Furthermore, optimizing the predictive model by including additional CYP2A6 alleles improves the fit of the model in an independent data set and provides a novel method of predicting the functional impact of alleles without direct metabolism measurements. Lastly, comprehensive genotyping and in vivo metabolism data are used to demonstrate that genome-wide significant associations between CPD and single nucleotide polymorphisms (SNPs) are the result of synthetic associations.

• Erratum to: Genetic Influences on Four Measures of Executive Functions and Their Covariation with General Cognitive Ability: The Older Australian Twins Study.

  Authors: Teresa Lee, Miriam A Mosing, Julie D Henry, Julian N Trollor, David Ames, Nicholas G Martin, Margaret J Wright, Perminder S Sachdev

  Behavior genetics. 03/2012;

• Conditional and joint multiple-SNP analysis of GWAS summary statistics identifies additional variants influencing complex traits.

  Authors: Jian Yang, Teresa Ferreira, Andrew P Morris, Sarah E Medland, Pamela A F Madden, Andrew C Heath, Nicholas G Martin, Grant W Montgomery, Michael N Weedon, Ruth J Loos, Timothy M Frayling, Mark I McCarthy, Joel N Hirschhorn, Michael E Goddard, Peter M Visscher

  Nature genetics. 03/2012; 44(4):369-75.

  We present an approximate conditional and joint association analysis that can use summary-level statistics from a meta-analysis of genome-wide association studies (GWAS) and estimated linkageWe present an approximate conditional and joint association analysis that can use summary-level statistics from a meta-analysis of genome-wide association studies (GWAS) and estimated linkage disequilibrium (LD) from a reference sample with individual-level genotype data. Using this method, we analyzed meta-analysis summary data from the GIANT Consortium for height and body mass index (BMI), with the LD structure estimated from genotype data in two independent cohorts. We identified 36 loci with multiple associated variants for height (38 leading and 49 additional SNPs, 87 in total) via a genome-wide SNP selection procedure. The 49 new SNPs explain approximately 1.3% of variance, nearly doubling the heritability explained at the 36 loci. We did not find any locus showing multiple associated SNPs for BMI. The method we present is computationally fast and is also applicable to case-control data, which we demonstrate in an example from meta-analysis of type 2 diabetes by the DIAGRAM Consortium.

• 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.

• Common heritable contributions to low-risk trauma, high-risk trauma, posttraumatic stress disorder, and major depression.

  Authors: Carolyn E Sartor, Julia D Grant, Michael T Lynskey, Vivia V McCutcheon, Mary Waldron, Dixie J Statham, Kathleen K Bucholz, Pamela A F Madden, Andrew C Heath, Nicholas G Martin, Elliot C Nelson

  Archives of general psychiatry. 03/2012; 69(3):293-9.

  Understanding the relative contributions of genetic and environmental factors to trauma exposure, posttraumatic stress disorder (PTSD), and major depressive disorder (MDD) is critical to developingUnderstanding the relative contributions of genetic and environmental factors to trauma exposure, posttraumatic stress disorder (PTSD), and major depressive disorder (MDD) is critical to developing etiologic models of these conditions and their co-occurrence. To quantify heritable influences on low-risk trauma, high-risk trauma, PTSD, and MDD and to estimate the degree of overlap between genetic and environmental sources of variance in these 4 phenotypes. Adult twins and their siblings were ascertained from a large population-based sample of female and male twin pairs on the basis of screening items for childhood sexual abuse and physical abuse obtained in a previous assessment of this cohort. Structured psychiatric telephone interviews. Total sample size of 2591: 996 female and 536 male twins; 625 female and 434 male nontwin siblings. Main Outcome Measure Lifetime low- and high-risk trauma exposure, PTSD, and MDD. In the best-fitting genetic model, 47% of the variance in low-risk trauma exposure and 60% of the variance in high-risk trauma exposure was attributable to additive genetic factors. Heritable influences accounted for 46% of the variance in PTSD and 27% of the variance in MDD. An extremely high degree of genetic overlap was observed between high-risk trauma exposure and both PTSD (r = 0.89; 95% CI, 0.78-0.99) and MDD (r = 0.89; 95% CI, 0.77-0.98). Complete correlation of genetic factors contributing to PTSD and to MDD (r = 1.00) was observed. The evidence suggests that almost all the heritable influences on high-risk trauma exposure, PTSD, and MDD, can be traced to the same sources; that is, genetic risk is not disorder specific. Individuals with a positive family history of either PTSD or MDD are at elevated risk for both disorders and should be closely monitored after a traumatic experience for symptoms of PTSD and MDD.

• A Genome-Wide Study on the Perception of the Odorants Androstenone and Galaxolide.

  Authors: Antti Knaapila, Gu Zhu, Sarah E Medland, Charles J Wysocki, Grant W Montgomery, Nicholas G Martin, Margaret J Wright, Danielle R Reed

  Chemical senses. 02/2012;

  Twin pairs and their siblings rated the intensity of the odorants amyl acetate, androstenone, eugenol, Galaxolide, mercaptans, and rose (N = 1573). Heritability was established for ratings ofTwin pairs and their siblings rated the intensity of the odorants amyl acetate, androstenone, eugenol, Galaxolide, mercaptans, and rose (N = 1573). Heritability was established for ratings of androstenone (h(2) = 0.30) and Galaxolide (h(2) = 0.34) but not for the other odorants. Genome-wide association analysis using 2.3 million single nucleotide polymorphisms indicated that the most significant association was between androstenone and a region without known olfactory receptor genes (rs10966900, P = 1.2 × 10(-7)). A previously reported association between the olfactory receptor OR7D4 and the androstenone was not detected until we specifically typed this gene (P = 1.1 × 10(-4)). We also tested these 2 associations in a second independent sample of subjects and replicated the results either fully (OR7D4, P = 0.00002) or partially (rs10966900, P = 0.010; N = 266). These findings suggest that 1) the perceived intensity of some but not all odorants is a heritable trait, 2) use of a current genome-wide marker panel did not detect a known olfactory genotype-phenotype association, and 3) person-to-person differences in androstenone perception are influenced by OR7D4 genotype and perhaps by variants of other genes.

• Genetic Influences on Four Measures of Executive Functions and Their Covariation with General Cognitive Ability: The Older Australian Twins Study.

  Authors: Teresa Lee, Miriam A Mosing, Julie D Henry, Julian N Trollor, David Ames, Nicholas G Martin, Margaret J Wright, Perminder S Sachdev

  Behavior genetics. 02/2012;

  "Executive functions" (EF) is a multidimensional construct which encompasses many higher-order cognitive control operations, and is considered a potential mediator of age-associated changes in other"Executive functions" (EF) is a multidimensional construct which encompasses many higher-order cognitive control operations, and is considered a potential mediator of age-associated changes in other cognitive domains. Here we examine the heritability of four measures of EF, and the genetic influences on their covariation with general cognitive abilities (GCA) from the Older Australian Twins Study. Participants included 117 pairs of monozygotic twins, 98 pairs of dizygotic twins, and 42 single twins, with a mean age of 71. Genetic modeling showed that additive genetic factors contributed to 59, 63, 29, and 31% of the variance in the four measures: working memory, verbal fluency, response inhibition and cognitive flexibility, respectively. The phenotypic associations among the four EF measures were modest, which is in line with other evidence that EF is a multi-dimensional construct. All of the covariation between the EF measures was attributable to a common genetic factor. Similarly, all of the covariation between EF and General Cognitive Ability was explained by a common genetic factor, with no significant covariance due to environmental (E) factors. The genetic correlations between the measures were moderately high, suggesting that they may have common biological underpinnings. The genetic influence in the covariation of the EF measures and GCA also suggests that some aspects of EF and GCA share the same genes or same set of genes.

• Meta-analysis combining new and existing data sets confirms that the TERT-CLPTM1L locus influences melanoma risk.

  Authors: Matthew H Law, Grant W Montgomery, Kevin M Brown, Nicholas G Martin, Graham J Mann, Nicholas K Hayward, Stuart MacGregor

  The Journal of investigative dermatology. 02/2012; 132(2):485-7.

• 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.

• Brain structure in healthy adults is related to serum transferrin and the H63D polymorphism in the HFE gene.

  Authors: Neda Jahanshad, Omid Kohannim, Derrek P Hibar, Jason L Stein, Katie L McMahon, Greig I de Zubicaray, Sarah E Medland, Grant W Montgomery, John B Whitfield, Nicholas G Martin, Margaret J Wright, Arthur W Toga, Paul M Thompson

  Proceedings of the National Academy of Sciences of the United States of America. 01/2012;

  Control of iron homeostasis is essential for healthy central nervous system function: iron deficiency is associated with cognitive impairment, yet iron overload is thought to promoteControl of iron homeostasis is essential for healthy central nervous system function: iron deficiency is associated with cognitive impairment, yet iron overload is thought to promote neurodegenerative diseases. Specific genetic markers have been previously identified that influence levels of transferrin, the protein that transports iron throughout the body, in the blood and brain. Here, we discovered that transferrin levels are related to detectable differences in the macro- and microstructure of the living brain. We collected brain MRI scans from 615 healthy young adult twins and siblings, of whom 574 were also scanned with diffusion tensor imaging at 4 Tesla. Fiber integrity was assessed by using the diffusion tensor imaging-based measure of fractional anisotropy. In bivariate genetic models based on monozygotic and dizygotic twins, we discovered that partially overlapping additive genetic factors influenced transferrin levels and brain microstructure. We also examined common variants in genes associated with transferrin levels, TF and HFE, and found that a commonly carried polymorphism (H63D at rs1799945) in the hemochromatotic HFE gene was associated with white matter fiber integrity. This gene has a well documented association with iron overload. Our statistical maps reveal previously unknown influences of the same gene on brain microstructure and transferrin levels. This discovery may shed light on the neural mechanisms by which iron affects cognition, neurodevelopment, and neurodegeneration.

• Evidence of Differential Allelic Effects between Adolescents and Adults for Plasma High-Density Lipoprotein.

  Authors: Rita P S Middelberg, Andrew C Heath, Pamela A F Madden, Grant W Montgomery, Nicholas G Martin, John B Whitfield

  PloS one. 01/2012; 7(4):e35605.

  A recent meta-analysis of genome-wide association (GWA) studies identified 95 loci that influence lipid traits in the adult population and found that collectively these explained about 25-30% ofA recent meta-analysis of genome-wide association (GWA) studies identified 95 loci that influence lipid traits in the adult population and found that collectively these explained about 25-30% of heritability for each trait. Little is known about how these loci affect lipid levels in early life, but there is evidence that genetic effects on HDL- and LDL-cholesterol (HDL-C, LDL-C) and triglycerides vary with age. We studied Australian adults (N = 10,151) and adolescents (N = 2,363) who participated in twin and family studies and for whom we have lipid phenotypes and genotype information for 91 of the 95 genetic variants. Heterogeneity tests between effect sizes in adult and adolescent cohorts showed an excess of heterogeneity for HDL-C (p(Het)<0.05 at 5 out of 37 loci), but no more than expected by chance for LDL-C (1 out of 14 loci), or trigycerides (0 out 24). There were 2 (out of 5) with opposite direction of effect in adolescents compared to adults for HDL-C, but none for LDL-C. The biggest difference in effect size was for LDL-C at rs6511720 near LDLR, adolescents (0.021±0.033 mmol/L) and adults (0.157±0.023 mmol/L), p(Het) = 0.013; followed by ZNF664 (p(Het) = 0.018) and PABPC4 (p(Het) = 0.034) for HDL-C. Our findings suggest that some of the previously identified variants associate differently with lipid traits in adolescents compared to adults, either because of developmental changes or because of greater interactions with environmental differences in adults.

• 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.