Margaret J Wright

Publications of Margaret J Wright

• 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.

• The heritability of brain metabolites on proton magnetic resonance spectroscopy in older individuals.

  Authors: Seyed Amir Hossein Batouli, Perminder S Sachdev, Wei Wen, Margaret J Wright, Chao Suo, David Ames, Julian N Trollor

  NeuroImage. 04/2012;

  Twin studies have shown that many aspects of brain structure are heritable, suggesting a strong genetic contribution to brain structure. Less is known about functional aspects of the brain, inTwin studies have shown that many aspects of brain structure are heritable, suggesting a strong genetic contribution to brain structure. Less is known about functional aspects of the brain, in particular biologically relevant metabolites in the brain such as those measured by proton magnetic resonance spectroscopy (((1))H MRS), N-acetyl-aspartate (NAA), creatine (Cr), choline (Cho) and myoinositol (ml), which have been suggested as possible markers of brain aging and early dementia. We examined 296 (56 male/108 female monozygotic and 43 male/89 female dizygotic) older twins (mean age 72.2±5.5years, range 65-88), for the levels of these metabolites relative to the H(2)O signal in the posterior cingulate cortex using ((1))H MRS. All metabolites showed substantial heritability, which was greatest for the neuronal integrity marker NAA (72%), and less so for the others - Cr (51%), Cho (33%) and ml (55%). The heritability of these markers did not change significantly with age or sex. The genetic determination of NAA, along with the evidence that NAA levels change in aging and neurodegenerative diseases suggest that it is a potential endophenotype of brain aging and dementia.

• 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.

• 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;

• 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.

• 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.

• 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.

• Genetic influences on life span and its relationship to personality: a 16-year follow-up study of a sample of aging twins.

  Authors: Miriam A Mosing, Sarah E Medland, Allan McRae, Joseph George Landers, Margaret J Wright, Nicholas G Martin

  Psychosomatic medicine. 12/2011; 74(1):16-22.

  The relationship between personality and life span is not well understood, and no study to date has examined genetic influences underlying this relationship. The present study aimed to explore theThe relationship between personality and life span is not well understood, and no study to date has examined genetic influences underlying this relationship. The present study aimed to explore the phenotypic and genetic relationship between personality and life span, as well as genetic influences on all-cause mortality. Prospective community-based study including 3752 twin individuals older than 50 years. Neuroticism, psychoticism, extraversion, and social desirability and pessimism/optimism were measured at baseline using the Revised Eysenck Personality Questionnaire and the Revised Life Orientation Test, respectively. Information on age at death was obtained 16 years after the initial assessment of personality. Extraversion was inversely related to mortality with the risk of death decreasing 3% per unit increase of the extraversion score. Psychoticism and pessimism were positively related to mortality with a 36% and 39% increase in risk of death per unit increase in the respective personality score. Heritability of life span was 7%. Cross-twin cross-trait hazard ratios (HRs) were only significant for optimism/pessimism in monozygotic (MZ) twins with no significant differences in HRs between MZ and dizygotic twins in all traits; however, there was a trend for slightly higher HRs in MZ compared with dizygotic twins in psychoticism and optimism/pessimism. Extraversion, psychoticism, and optimism/pessimism are significant predictors of longevity; extraversion is associated with a reduction, and pessimism and psychoticism are associated with an increase in mortality risk. Genetic influences on longevity in Australian twins are very low (7%). Our data also suggest a small, albeit nonsignificant, genetic influence on the relationship of pessimism and psychoticism with life span.

• Hierarchical topological network analysis of anatomical human brain connectivity and differences related to sex and kinship.

  Authors: Julio M Duarte-Carvajalino, Neda Jahanshad, Christophe Lenglet, Katie L McMahon, Greig I de Zubicaray, Nicholas G Martin, Margaret J Wright, Paul M Thompson, Guillermo Sapiro

  NeuroImage. 11/2011; 59(4):3784-804.

  Modern non-invasive brain imaging technologies, such as diffusion weighted magnetic resonance imaging (DWI), enable the mapping of neural fiber tracts in the white matter, providing a basis toModern non-invasive brain imaging technologies, such as diffusion weighted magnetic resonance imaging (DWI), enable the mapping of neural fiber tracts in the white matter, providing a basis to reconstruct a detailed map of brain structural connectivity networks. Brain connectivity networks differ from random networks in their topology, which can be measured using small worldness, modularity, and high-degree nodes (hubs). Still, little is known about how individual differences in structural brain network properties relate to age, sex, or genetic differences. Recently, some groups have reported brain network biomarkers that enable differentiation among individuals, pairs of individuals, and groups of individuals. In addition to studying new topological features, here we provide a unifying general method to investigate topological brain networks and connectivity differences between individuals, pairs of individuals, and groups of individuals at several levels of the data hierarchy, while appropriately controlling false discovery rate (FDR) errors. We apply our new method to a large dataset of high quality brain connectivity networks obtained from High Angular Resolution Diffusion Imaging (HARDI) tractography in 303 young adult twins, siblings, and unrelated people. Our proposed approach can accurately classify brain connectivity networks based on sex (93% accuracy) and kinship (88.5% accuracy). We find statistically significant differences associated with sex and kinship both in the brain connectivity networks and in derived topological metrics, such as the clustering coefficient and the communicability matrix.

• 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.

• Cognitive functioning in older twins: the Older Australian Twins Study.

  Authors: Perminder S Sachdev, Teresa Lee, Andrea Lammel, John Crawford, Julian N Trollor, Margaret J Wright, Henry Brodaty, David Ames, Nicholas G Martin

  Australasian journal on ageing. 10/2011; 30 Suppl 2:17-23.

  To examine the concordance rates of common medical conditions and neurocognitive performance in monozygotic (MZ) and dizygotic (DZ) older twins. Twins aged ≥ 65 years and living in the three EasternTo examine the concordance rates of common medical conditions and neurocognitive performance in monozygotic (MZ) and dizygotic (DZ) older twins. Twins aged ≥ 65 years and living in the three Eastern states of Australia were recruited through the Australian Twin Registry and underwent detailed neuropsychological and medical assessment. Assessments were conducted on 113 MZ and 96 DZ twin pairs, with a mean age of 70.5 years. MZ twins were more concordant than DZ twins for hypertension and asthma. MZ twins had higher correlations than DZ twins on most neuropsychological tests, with the exception of some tests related to processing speed. The concordance rate for mild cognitive impairment or dementia was 76.2% in MZ twins and 42.9% in DZ twins, a non-significant difference. Except for some aspects of processing speed, most cognitive functions in older individuals show significant heritability. The heritability of neurocognitive disorders is, however, low.

• 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.

• Heritability of working memory brain activation.

  Authors: Gabriëlla A M Blokland, Katie L McMahon, Paul M Thompson, Nicholas G Martin, Greig I de Zubicaray, Margaret J Wright

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 07/2011; 31(30):10882-90.

  Although key to understanding individual variation in task-related brain activation, the genetic contribution to these individual differences remains largely unknown. Here we report voxel-by-voxelAlthough key to understanding individual variation in task-related brain activation, the genetic contribution to these individual differences remains largely unknown. Here we report voxel-by-voxel genetic model fitting in a large sample of 319 healthy, young adult, human identical and fraternal twins (mean ± SD age, 23.6 ± 1.8 years) who performed an n-back working memory task during functional magnetic resonance imaging (fMRI) at a high magnetic field (4 tesla). Patterns of task-related brain response (BOLD signal difference of 2-back minus 0-back) were significantly heritable, with the highest estimates (40-65%) in the inferior, middle, and superior frontal gyri, left supplementary motor area, precentral and postcentral gyri, middle cingulate cortex, superior medial gyrus, angular gyrus, superior parietal lobule, including precuneus, and superior occipital gyri. Furthermore, high test-retest reliability for a subsample of 40 twins indicates that nongenetic variance in the fMRI brain response is largely due to unique environmental influences rather than measurement error. Individual variations in activation of the working memory network are therefore significantly influenced by genetic factors. By establishing the heritability of cognitive brain function in a large sample that affords good statistical power, and using voxel-by-voxel analyses, this study provides the necessary evidence for task-related brain activation to be considered as an endophenotype for psychiatric or neurological disorders, and represents a substantial new contribution to the field of neuroimaging genetics. These genetic brain maps should facilitate discovery of gene variants influencing cognitive brain function through genome-wide association studies, potentially opening up new avenues in the treatment of brain disorders.

• SNP sets and reading ability: testing confirmation of a 10-SNP set in a population sample.

  Authors: Michelle Luciano, Grant W Montgomery, Nicholas G Martin, Margaret J Wright, Timothy C Bates

  Twin research and human genetics : the official journal of the International Society for Twin Studies. 06/2011; 14(3):228-32.

  A set of 10 SNPs associated with reading ability in 7-year-olds was reported based on initial pooled analyses of 100K SNP chip data, with follow-up testing stages using pooling and individualA set of 10 SNPs associated with reading ability in 7-year-olds was reported based on initial pooled analyses of 100K SNP chip data, with follow-up testing stages using pooling and individual testing. Here we examine this association in an adolescent population sample of Australian twins and siblings (N = 1177) aged 12 to 25 years. One (rs1842129) of the 10 SNPs approached significance (P = .05) but no support was found for the remaining 9 SNPs or the SNP set itself. Results indicate that these SNPs are not associated with reading ability in an Australian population. The results are interpreted as supporting use of much larger SNP sets in common disorders where effects are small.

• Genetic influences on five measures of processing speed and their covariation with general cognitive ability in the elderly: the older Australian twins study.

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

  Behavior genetics. 05/2011; 42(1):96-106.

  Processing speed (PS) is one of the basic elements of cognitive functions and has been regarded as a "common mechanism" which mediates general cognitive decline in aging. The present study ofProcessing speed (PS) is one of the basic elements of cognitive functions and has been regarded as a "common mechanism" which mediates general cognitive decline in aging. The present study of Australian twins (117 monozygotic pairs, 98 dizygotic pairs, and 42 single twins aged 65 years and over), estimated the genetic influences in five measures of PS: Digit Symbol Coding (DS), Trail Making Test A (TMTA), Stroop color naming and word reading (Stroop), Simple Reaction Time (SRT) and Complex Reaction Time (CRT); and their covariation with general cognitive ability (GCA): reasoning, problem-solving, and memory. Additive genetic factors explained 62% of the variance in DS, 42% in TMTA, 57% in Stroop, and 48% and 35% in SRT and CRT, respectively. Quantitative genetic modeling showed that all of the covariation between the five PS measures and GCA could be explained by one common genetic factor, while the covariation between the PS measures was partly explained by non-shared environmental as well as genetic influences. The genetic correlation among the PS measures was strongest for DS and TMTA, and between the PS measures and GCA was strongest for DS. These findings suggest that the different PS measures, as well as GCA were to a large extent influenced by the same set of genes and that the relationship between PS and GCA is entirely due to shared-genetic influences.

• Common Alzheimer's disease risk variant within the CLU gene affects white matter microstructure in young adults.

  Authors: Meredith N Braskie, Neda Jahanshad, Jason L Stein, Marina Barysheva, 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. 05/2011; 31(18):6764-70.

  There is a strong genetic risk for late-onset Alzheimer's disease (AD), but so far few gene variants have been identified that reliably contribute to that risk. A newly confirmed genetic risk alleleThere is a strong genetic risk for late-onset Alzheimer's disease (AD), but so far few gene variants have been identified that reliably contribute to that risk. A newly confirmed genetic risk allele C of the clusterin (CLU) gene variant rs11136000 is carried by ∼88% of Caucasians. The C allele confers a 1.16 greater odds of developing late-onset AD than the T allele. AD patients have reductions in regional white matter integrity. We evaluated whether the CLU risk variant was similarly associated with lower white matter integrity in healthy young humans. Evidence of early brain differences would offer a target for intervention decades before symptom onset. We scanned 398 healthy young adults (mean age, 23.6 ± 2.2 years) with diffusion tensor imaging, a variation of magnetic resonance imaging sensitive to white matter integrity in the living brain. We assessed genetic associations using mixed-model regression at each point in the brain to map the profile of these associations with white matter integrity. Each C allele copy of the CLU variant was associated with lower fractional anisotropy--a widely accepted measure of white matter integrity--in multiple brain regions, including several known to degenerate in AD. These regions included the splenium of the corpus callosum, the fornix, cingulum, and superior and inferior longitudinal fasciculi in both brain hemispheres. Young healthy carriers of the CLU gene risk variant showed a distinct profile of lower white matter integrity that may increase vulnerability to developing AD later in life.