Julien Amendola, Pierre L. Roubertoux, Bernard Verrier and Jacques Durand. Altered sensorimotor development in SOD1G85R transgenic mice, a model of amyotrophic lateral sclerosis

ADDRESS : CNRS, Marseille Plasticité et Physiopathologie de la Motricité, UMR 6196 CNRS / Université de la Méditerranée 31, Chemin Joseph Aiguier 13402 Marseille Cedex 20, France¹ E-mail : julien.amendola@libertysurf.fr

Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disease affecting motoneurons in the cortex, brainstem and spinal cord. The SOD1^G85R transgenic mice, expressing familial amyotrophic lateral sclerosis (ALS)-linked mutation G85R in the human gene encoding Cu-Zn superoxide dismutase 1 (SOD1) develop an ALS-like disease characterized by an extremely rapid clinical course resulting from the loss of motor neurons. Despite several cellular mecanisms related to the degeneration have been proposed, the early alterations triggering the toxic pathways remain poorly documented. We addressed the question of whether the SOD1 mutation affects sensorimotor processes during the maturation of spinal motor networks. Behavioural tests revealed that appearance of some sensorimotor reflexes are significantly shifted in SOD1^G85R newborn pups compared to wild-type (WT) mice (C57Bl/6J). Furthermore, following bath-application of N-methyl-DL-aspartate (NMA) and serotonin (5-HT), the motor output extracellularly recorded from lumbo-sacral ventral roots in an in vitro brainstem/spinal cord preparation obtained from newborn mice demonstrated a hypoexcitability in SOD1^G85R lumbar motor networks. The results also suggests that sacral networks in which some motoneurons are spared in ALS are not affected in this postnatal period. Taken together, these results strongly support the idea that the G85R mutation affects the maturation of lumbar spinal motor networks in which motoneurons degenerate massively in adult animals.

Juko Ando¹, Ryoko Nakajima¹, Yutaka Ono ², Kimio Yoshimura³, Nobuhiko Kijima⁴, Kato Rumi Price⁵. Genetic influences on smoking and drinking behaviors in Japanese adolescence and young adulthood: A twin study ⁶

¹ Faculty of Letters, Keio University, Minato-ku Tokyo, Japan, ² Health Center, Keio University, Yokohama Kanagawa, Japan, ³ National Cancer Center, Chuo-ku Tokyo, Japan, ⁴ Psychological Laboratory, Keio University, Yokohama Kanagawa, Japan, ⁵ Washington University School of Medicine, St. Louis, USA, 6 Supported by a Grant-in Aid for Scientific Research (A) from the Ministry of Education, Science, Sports and Culture.

Address : :Faculty of Letters, Keio University, 2-15-45, Mita, Minatob-ku, Tokyo, 108-8345, Japan Telehone: 81 3 3453 4511 Fax: 81 3 5427 1578 Email: juko@msa.biglobe.ne.jp

Genetic influences on smoking and drinking behaviors were investigated by 335 Japanese twin pairs (157 MZf, 41 DZf, 72 MZm, 24 DZm, and 41 DZo; mean age = 20.4 yrs (SD=4.2)). Smoking status (current smoker / past smoker / non smoker) and frequency of drinking showed greater MZ similarity than DZ similarity (rMZ=.46 and rDZ=.24 for smoking status; rMZ=.59 and rDZ=.16 for frequency of drinking), indicating genetic contribution. For smoking status, however, there might be gender difference indicating that genetic contribution is found only for female (rMZf=.53, rDZf=.07, rMZm=.30, rDZm=.44). For frequency of drinking, both female and male showed substantial genetic influences (rMZf=.52, rDZf=.14, rMZm=.72, rDZm=.45, rDZo=.14), and these genetic influences were found even for minors(under 20 yrs old) who are not allowed to drink legally. There is no genetic comobidity between smoking status and drinking frequency.

Andrey P. Anokhin¹, Andrew C. Heath¹, and Erin Myers¹. Genetic influences on neurocognitive mechanisms of inhibitory control: a twin study of event-related brain potentials (ERPs) in a Go/No-Go task².

¹Washington University School of Medicine, St. Louis MO USA, ²Supported by the grants DA00421 from the National Institute on Drug Abuse and a pilot grant from the Missouri Alcoholism Research Center (P50 AA11998).

Address : Washington University School of Medicine, Department of Psychiatry, 18 S. Kingshighway, Suite 2T, St.Louis, MO 63108 USA Telephone: 314-286-2201; FAX: 314-286-0092; email: andrey@matlock.wustl.edu

Inhibition of prepotent responses plays a key role in cognitive control of goal-directed behavior and can be studied experimentally using the Go/No-Go paradigm which requires a speeded response to the Go stimuli and withholding a prepotent response when a No-Go stimulus is presented. Response inhibition in Go-NoGo tasks elicits a distinct mid-frontal ERP component, the N2, localized by recent electrophysiological and neuroimaging studies to the anterior cingulate cortex, and a strong enhancement of the frontal P3 component known as "P3 anteriorization". The N2 effect is believed to reflect the processing by the anterior cingulate of the conflict between competing but incompatible action tendencies. We assessed heritability of the No-Go N2 and the succeeding positive P3 component in 194 young female twins (52 monozygotic and 45 dizygotic pairs) who completed a cued version of the Continuous Performance Test. The ERPs were computed separately for Go and No-Go trials. Genetic model-fitting analysis showed that about 60% of variance in the amplitude of No-Go N2 and P3 components can be attributed to genetic factors. The results suggest that frontal No-Go N2 and P3 components are indicative of genetically transmitted individual differences in the neural substrates of conflict monitoring and response inhibition. These electrophysiological markers can potentially serve as endophenotypes for genetic studies of psychopathologies characterized by executive deficits and behavioral disinhibition.

Andrey P. Anokhin¹, Andrew C. Heath¹, and Erin Myers¹. Heritability of Behavioral Approach and Inhibition Systems (BIS/BAS) scales in twins².

¹Washington University School of Medicine, St. Louis MO USA, ²Supported by the grants DA00421 from the National Institute on Drug Abuse and a pilot grant from the Missouri Alcoholism Research Center (P50 AA11998).

Address : Washington University School of Medicine, Department of Psychiatry, 18 S. Kingshighway, Suite 2T, St.Louis, MO 63108 USA

Telephone: 314-286-2201; FAX: 314-286-0092; email: andrey@matlock.wustl.edu

We examined the genetic and environmental etiology of individual differences in the strength of hypothesized Behavioral Approach and Inhibition Systems (BAS and BIS) based on work by Gray (J.A.Gray, 1990, Cognition and Emotion, 4, 269-288). A modified self-report measure of BIS/BAS (C.S.Carver and T.L.White, 1994, J. Pers. Soc. Psychol. 67, 319-333) was administered to 212 young adult female twins (age 18-28) including 55 MZ and 51 DZ pairs. A biometrical genetic analysis using structural equation modeling showed significant heritability of BIS and BAS scores, suggesting that about 50% of variance in both measures can be explained by genetic factors. The balance between the two systems as measured by BAS-BIS difference score was also heritable. Two of the three individual subscales composing the BAS scale, Fun Seeking and Drive, showed significant heritability, whereas Reward Responsiveness did not. These preliminary results suggest a substantial contribution of genetic factors to individual differences in the sensitivity to signals of reward and punishment as assessed by BIS/BAS scales.

Laura A. Baker, Adrian Raine¹ and Kristen Jacobson. Genetic and environmental bases of pre-adolescent antisocial behavior: A multi-trait multi-method twin study.

¹Department of Psychology, University of Southern California, Los Angeles, CA USA. NIMH #MH58354

Address : University Park Campus, Los Angeles, CA 90089 Telephone: 213 740 2261 Fax: 213 746 9082 E-mail: lbaker@usc.edu

This paper describes the first wave of assessment in a new twin study of normal variation in antisocial and aggressive behavior (ASB). Data are presented from 600 twin pairs (both male and female) measured at age 9-10 years old, and their primary caregivers (over 90% biological mothers). Measures of ASB and aggression include symptom counts for conduct disorder and oppositional defiant disorder, as well as ratings of proactive and reactive aggression, relational aggression, CBCL scales for delinquency and aggression, a child psychopathy checklist, and a child delinquency interview. A multi-informant approach is used, based on child self reports, as well as teacher and caregiver ratings. Boys appeared significantly more aggressive and antisocial than girls for all measures across raters. The various ASB measures were moderately correlated within informants, but less so across informants, suggesting the possibility of generalized antisocial behavior factor with significant variation across raters. First principal component measures of the ASB measures within each rater all showed significant genetic and shared environmental influences in both boys and girls. Heritability estimates for individual ASB measures varied considerably, however, both within and between raters, suggesting specificity of etiologies for different definitions of ASB and the informants who provide the ASB ratings.

David A. Blizard,¹ David J. Vandenbergh,^{1, 2} Arimantas Lionikas,¹ Glenn S. Gerhard³, James W. Griffith,⁴ Laura C. Klein ^1,2, Joseph T. Stout,¹ Holly A. Mack^1,2, Joan M. Lakoski,⁵ Lars Larsson,⁶ Jeanne M. Spicer¹, George P. Vogler^1,2 and Gerald E. McClearn^1,2 . QTL influencing standard deviation of heart rate and blood pressure in the mouse.

¹Center for Developmental & Health Genetics,and ²Department of Biobehavioral Health, The Pennsylvania State University, University Park, Pennsylvania USA, ³Geisinger Medical Center, Weis Center for Research, Danville, Pennsylvania USA, ⁴ Department of Comparative Medicine, Pennsylvania State College of Medicine, Hershey, Pennsylvania USA, ⁵University of Pittsburgh, Department of Health Sciences, Pittsburgh, Pennsylvania USA, ⁶Department of Clinical Neurophysiology, Uppsala University, Uppsala, Sweden.

This work was supported by grants P01 AG14731 and T32 AG00276 from the National Institute on Aging of the National Institutes of Health.

ADDRESS : Center for Developmental and Health Genetics, 201, Research Bldg D, Pennsylvania State University, University Park, PA, 16802.

Telephone: 814-865-3429 Fax 814-863-4768 E-mail : dab22@psu.edu

Using indirect tail-cuff determinations systolic blood pressure and heart rate were recorded from nearly 400 male and female F₂s derived from a cross of C57BL/6J and DBA/2J mice and from 22 BXD RI strains at approximately 150 days of age. Recordings were obtained on 7 days with 3 blocks of 8 measurements per day for a maximum of 154 readings per F₂ mouse (5 days of readings in RIs). Standard deviations (SDs) were calculated for each 8 trial block for each mouse and mean SD for each mouse over all days used as primary datum for QTL analysis. Analysis with QTL Cartographer revealed the presence of three QTL contributing to the magnitude of within animal HR and BP SDs (SBP, peak at 33 cMs on Chr 9, 1-LOD support interval, 27-41 cms; HR, two peaks at 28 and 50 cMs on Chr 8 with support intervals, 17-37 and 39-60 cM, respectively; peak at 40 cM on Chr18, support interval, 18-55 cM). The HR SD on Chr 8 (proximal QTL) was verified by analysis of RI strains. Analysis of variance of a struggling index (SI) at markers near the QTL peaks revealed a significant effect of D18Mit123 (the marker at the HR SD peak on Chr 18; F, 2, 368 = 7.2, p<0.001). Animals homozygous for the B6 allele at this marker had higher SI than heterozygotes or D2D2 homozygotes, exactly the same pattern as that exhibited for the HR SD QTL on Chr 18. These QTL influencing within animal HR and SBP variability were on different chromosomes than QTL that influenced mean level of these functions (reported elsewhere). Physiological mechanisms that could account for differences in HR and BP variability will be discussed as well as possible pathophysiological consequences of individual differences in the magnitude of cardiovascular variability

Dorett I. Boomsma¹, C.E.M. van Beijsterveldt¹, E.M. Derks¹, M. Bartels¹, and J.J. Hudziak². Shared environmental factors involved in Anxiety/Depression during childhood: real or inflated by rater bias? A study from The Netherlands Twin Register.³

¹Department of Biological Psychology, Vrije Universiteit, Amsterdam, The Netherlands, ²Department of Psychiatry and Medicine (Division of Human Genetics), Center for Children, Youth and Families, and University of Vermont, College of Medicine, Burlington, USA, ³Supported by NWO Spinoza Grant numbers SPI-56-464 (Boomsma, P.I.) and by NIMH Grant number MH58799 (Hudziak, P.I.)

Address : Vrije Universiteit, Department of Biological Psychology, van der Boechorststraat 1, 1081 BT Amsterdam, The Netherlands, Telephone: 0031(0)20-4448787 Fax: 0031(0)20-4448832 Email: dorret@psy.vu.nl

In our longitudinal studies of problem behavior we find evidence for an increasing role of shared environment influencing Anxiety/Depression (A/D) during childhood. Because these results were based on a single rater, it is possible that rater bias may have inflated the role of shared environmental influences. To disentangle the effects of rater bias and unreliability from that of shared and nonshared environmental factors, we used a psychometric model incorporating both paternal and maternal ratings. The psychometric model assumes that part of the assessment of the child=s behavior is rater-specific and part is common to both raters. The part that is common to both parents contains only reliable variance. Rater bias can only confound the shared environmental influences specific to one parent. At ages 3, 5, 7, 10 and 12 years indices of A/D were obtained from maternal and paternal CBCL ratings (at age 5, anxiety was obtained from Devereux Child Behavior rating scale items) as part of a large ongoing longitudinal study of the Netherlands Twin Register (NTR). At ages 3 and 5 years data are available for around 9000 twin pairs; at 7, 10 and 12 years for around 7300, 4400 and 2400 pairs. Rater-specific shared environment, including rater bias, accounted for 0-19% of the total variance and was nearly absent at age 3 and strongest at age 7. When only the reliable part of A/D is taken into account, the role of environmental factors decreased at all ages, but the initial pattern of increasing influence during childhood remained. Heritability became smaller (around 70% at age 3 and around 40% at age 12 years) but remained the most important factor in explaining the variance of A/D across ages.

Dorret I. Boomsma¹, Gonneke Willemsen¹, Eco J.C. de Geus¹, Louise C. Hawkley², John T. Cacioppo², Danielle Posthuma¹. Genetics of Loneliness: A study from The Netherlands Twin Register.

¹Vrije Universiteit, Amsterdam, The Netherlands; ²University of Chicago, USA. This research was supported by NWO grants 575-25-006, 904-61-090,

985-10-002, 904-61-193 (Netherlands Organization for Scientific Research) and the National Institute of Aging Grant No. PO1 AG18911 (Social isolation, loneliness, health, and the aging process). Danielle Posthuma was supported by GenomEUtwin, European Union Contract No. QLG2-CT-2002-01254. Genotyping was carried out by the Center for Medical Genetics in Marshfield (research.marshfieldclinic.org/ genetics/).

Address : Biological Psychology, Vrije Universiteit, Van der Boechorststraat 1,

1081BT Amsterdam, The Netherlands, fax 31-20-4448832, Telephone 31-20-4448787, Email: dorret@psy.vu.nl

A measure of loneliness was obtained by factor analyses of YASR items (Achenbach, 1990, Young Adult Self Report. Univ Vermont, Dept Psychiatry, Burlington, VT). YASR items were assessed longitudinally in participants in the survey studies of the Netherlands Twin Register. The longitudinal stability of the loneliness measure ranged from 0.4 to 0.62 (2 to 9 year stability) in both males and females. Data on loneliness from 7,665 adolescent and (young) adult Dutch twins (average age 24 years) were analyzed with genetic structural equation models. The estimate of the genetic contribution to variation in loneliness was 47%, with the remaining variance explained by unique environmental factors. There was no evidence for sex differences in genetic architecture. A complete genome scan in a subsample of participants found evidence for 2 QTLs (LOD scores of > 3 and > 2).

Tanya M. M. Button,¹ Jane Scourfield,² Neilson Martin,³ Shaun Purcell^1,4 and Peter McGuffin^1. Family dysfunction interacts with genes in the causation of antisocial symptoms⁵. "

¹ Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King=s College, London UK, ² Department of Psychological Medicine, University of Wales College of Medicine, Cardiff UK, ³ School of Psychology, Curtin University, Perth, Western Australia, ⁴ Whitehead Institute, MIT, Cambridge, MA, USA, ⁵ Supported by the MRC via a training fellowship to JS and studentships to NM and TB.

MAIL: Social, Genetic, and Developmental Research Centre, Institute of Psychiatry, King's College London, De Crespigny Park, Denmark Hill, London SE5 8AF, England Telephone: +44 (0) 207 848 5415 Fax: +44 (0) 207 848 0575 E.mail: t.button@iop.kcl.ac.uk

There is emerging evidence of gene-environment interaction effects on antisocial behavior, both from adoption studies and from a study using a measured genotype. An association between non-violent family dysfunction and antisocial behavior has also been reported, although not in the context of gene-environment interaction studies. The aim of this study was to examine the interaction of genes and family dysfunction in contributing to antisocial behavior in young people. Parents of 278 monozygotic and 378 dizygotic twin pairs, aged 5-18, from the CaStANET birth cohort twin register were questioned about zygosity, antisocial behavior and family environment. Using structural equation modelling we tested for main and interactive effects of genes and family dysfunction modelled as an environmental >moderator variable=. Both main and gene-environment interaction effects were highly significant . It was concluded that a risk genotype conferring susceptibility to family dysfunction is responsible for most of the variance in antisocial symptoms in childhood and adolescence.

Desmond Campbell, Harvey E. Wickham, Pak C. Sham. Simulation-based estimation of genetic, environmental and overall liability scores from pedigree affection data for multifactorial disorders.

SGDP, Institute of Psychiatry, KCL, London, UK.

Address: Room C0.29, SGDP Centre, Institute of Psychiatry, De Crespigny Park, London SE5 8AF Telephone +44 (0) 20 7848 0236 Fax: +44 (0) 20 7848 0866 Email: D.Campbell@iop.kcl.ac.uk

In contrast to Mendelian disorders, there is presumed to be an underlying continuum of liability to categorically defined multifactorial polygenic disorders (D. S. Falconer, T. F. C. Mackay, 1989, Introduction to Quantitative Genetics). For such disorders, the use of diagnostic categories when searching for biological disease markers leads to a loss of power. This is due to a loss of information; pedigree members can be qualitatively healthy despite being carriers of disease susceptibility alleles. A more powerful approach would be to use continuous measures reflecting underlying genetic, environmental and overall liabilities to the disorder. A software program has been developed which, given a polygenic disease=s heritability, estimates these liabilities for the individuals in pedigrees with the disease by Gibb=s sampling. The program models age of onset effects and different prevalences in subpopulations (defined by age groups, gender, marital status, or any known risk factor) in a user-specified way. The resulting liability estimates can be related to endophenotypes (or putative risk factors) by a generalized least-squares regression framework. A general hypothesis testing framework allows the user to specify any linear null-hypothesis based on the estimated regression coefficients and their covariance matrix. This facilitates determining whether the discovered liability-risk factor relationships are statistically significant. Program operation has been verified using simulated pedigree data.

Gregory Carey¹. Cholesky Problems.

¹ Department of Psychology and Institute for Behavioral Genetics, University of Colorado, Boulder CO USA. Supported in part by NIH grant M01 RR00051.

Address : Department of Psychology, University of Colorado, Boulder CO, USA 80309-0345 Telephone: 303-492-1658 Fax: 303-492-2967 Email: gregory.carey@colorado.edu

Behavioral geneticists commonly parameterize a genetic or environmental covariance matrix as the product of a nonsingular, lower diagonal matrix postmultiplied by its transposeCa technique commonly referred to as Afitting a Cholesky.@ Here, simulations demonstrate that this procedure: (1) may not produce likelihood ratio test statistics that are distributed as a ?²; (2) if the distribution of the test statistic appears to be ?², then the degrees of freedom are not always the difference between the number of parameters in the general model less the number of parameters in the constrained model; and (3) confidence limits on parameters may be inaccurate. It is hypothesized that the problem is related to the fact that the Cholesky parameterization requires that the covariance matrix formed by its product be positive definite. Even though a population covariance matrix must be positive definite, the combination of sampling error and the derivedCas opposed to directly observedCnature of some matrices in behavioral genetics allow matrices that are not positive definite. Hence, fitting a Cholesky constrains the area of search and compromises maximum likelihood theory. Until the reason for this phenomenon is understood and a satisfactory solution is developed, the Cholesky parameterization should be used with caution. An alternate strategy of fitting a lower diagonal matrix to data that avoids the Cholelsky problem is proposed.

Michèle Carlier¹, Silvia Stefanini², Arianna Bello² and Virginia Volterra³. Prehension and Laterality in Children with Williams-Beuren Syndrome

¹ Laboratory PsyCLÉ, University of Provence, Aix en Provence, France, ²Department of Neuroscience, University of Parma, Italy, ³Institute of Cognitive Science and Technologies, National Research Council (CNR), Roma, Italy.

The study was supported by the FIRB/MIUR AAction and Perception in the construction of the cognitive world@ (RBNE01SZB4), the ESF EUROCORES program AThe Origin of Man, Language and Languages@, and the Fondation Jérôme Lejeune.

Address M. Carlier: Laboratory PsyCLÉ, UFR PSE, University of Provence, 29 Avenue Robert Schuman13621 Aix en Provence, France E-mail: michele.carlier@up.univ-aix.fr

Individuals with Williams-Beuren syndrome (WBS) show a characteristic cognitive profile with weakness in visuo-spatial cognition assessed for example with the Block Design from the Wechsler Intelligence Scales. Spatial working memory, flexibility in the use of spatial properties and in the hierarchical organization of objects are supposed to be involved in this task. However a special difficulty in fine motor abilities and in the development of object prehension could explain part of the low performance of these children. Here we investigate object prehension abilities and manual laterality in children with WBS, aspects which were not clearly described by previous studies. Prehension abilities and degree of laterality was investigated in children with WBS. Nine children with WBS, within a restricted age range (9-12 years) participated to the study. All were right handers for the writing hand. Perceptual and motor abilities were assessed with the Developmental Test of Visual-Motor Integration (VMI) ; manual dexterity was assessed with the Movement Assessment Battery for Children (M-ABC). Two tasks of the M-ABC afford a special opportunity to analyze the type of prehension adopted by children and to evaluate the direction and degree of manual laterality. Fourteen typically developing children constituted the comparison groups (all were right handers for the writing hand) : 6 were matched with WBS children for mental age and 8 for chronological age. All children except one in the group matched for mental age were right-handers (i.e., the right hand was better than the left). Children with WBS performed like younger typically developing children as for degree of laterality, but some of them adopted a peculiar type of prehension, never observed in the control groups. These findings on atypical prehension could provide a partial explanation of visual-motor difficulties exhibited by the children.

Xiangning Chen^1,3, Jaqueline M. Vink², Michael C. Neal¹, Kenneth S. Kendler¹ and Dorret I. Boomsma^2,3. A candidate study of the EPAC gene for nicotine dependence using a Dutch twin sample

¹ Virginia Institute for Psychiatric and Behavioral Genetics and Department of Psychiatry, USA, ² Department of Biological Psychiatry, Vrije Universiteit Amsterdam, 1081 BT Amsterdam, The Netherlands, ³ Corresponding authors. Email: xchen@vcu.edu (XC) and DI.Boomsma@fpp1.psy.vu.nl (DIB)

Address : Virginia Institute for Psychiatric and Behavioral Genetics and Department of Psychiatry, Virginia Commonwealth University, 800 E. Leigh Street, Suite 1-110, Richmond, VA 23298, USA. Telephone: 804 828 8124 Fax: 804 828 1471 Email: xchen@vcu.edu

The exchange protein directly activated by cAMP (EPAC) is a rap1 guanine-nucleotide exchange factor that involves in inter- and intracellular signal transduction pathway through the regulation of GTPase activity. It has been reported to have altered gene expression in rat in a microarray study after nicotine administration. In a case-control study, we recently investigated the human ortholog of the EPAC gene and found a modest association between the gene and nicotine dependence in a Caucasian sample collected in Virginia. In the Virginia sample we typed 5 SNPs and found that 3 SNPs and a haplotype were associated with nicotine dependence. To verifying our results, we are currently performing a replication study using a Dutch twin sample. The Dutch sample was ascertained similarly using the Fagerstrom Tolerance Questionnaires and other instruments as the Virginia sample. We are typing the 3 associated SNPs and will perform single marker and haplotype analyses to evaluate their association with nicotine dependence. The results of this replication will be presented in the meeting.

R. P. Corley¹, M. C. Stallings¹, J. K. Hewitt¹, S. E. Young¹, and J. Zeiger¹. Robustness of Genome Scan Results on Adolescent Dependence Vulnerability from the Colorado CADD².

¹Institute for Behavioral Genetics, University of Colorado, Boulder, CO USA, ²Supported by grants DA-05131 and DA-11015, HD-010333, HD-36773, and MH-43899

Address: Institute for Behavioral Genetics, Campus Box 447, University of Colorado, Boulder, CO 80309-0447 USA Telephone: 303 492 5189 Fax: 303 492 8063 Email: Robin.Corley@colorado.EDU

We previously presented (R. P. Corley, M. C. Stallings, J. K. Hewitt, & S. E. Young, 2001, Behavior Genetics, 31, 450) a comparative behavioral genetic analysis of ten potential phenotypic definitions of dependence vulnerability across multiple substances during adolescence and young adulthood. Based on the results from 3676 interviews of community samples of adopted & non-adopted siblings and twins, we chose one phenotypic definition on an a priori basis as our best initial choice of phenotype for a genome wide search for quantitative trait loci influencing substance dependence vulnerability in adolescent treatment probands and their siblings (M. C. Stallings, et al., 2003, Drug and Alcohol Dependence, 70, 295-307), in which regions of interest were identified on chromosomes 3 and 9. Through 2003, an additional 1613 interviews with 12- to 25- year olds have been completed from community samples. We use our combined community samples to explore the additive genetic contribution to six additional phenotypic definitions of dependence vulnerability, the similarity of age and gender effects in the additional adolescents with those found for the original sample, the effect of controlling for age and gender effects through multiple threshold and standard regression approaches, and whether comparable peaks on Chromosomes 3 and 9 are found across the spectrum of dependence vulnerability phenotypes in the treatment sample.

Victoria E. Cosgrove^1,2, Blake Buhlig^1,2, Soo Hyun Rhee^1,2, Susan E. Young¹, Andrew Smolen¹, Robin P. Corley¹, John K. Hewitt^1,2. Sibling-based association analyses of the serotonin transporter polymorphism and Generalized Anxiety Disorder in adolescents³.

¹Institute for Behavioral Genetics and ²Department of Psychology, University of Colorado, Boulder, CO, ³Supported by NIH grants MH-01865, DA-11015, HD-18426, MH-43899, and DA-13956 and funding from the John D. and Catherine T. MacArthur Foundation.

Address : Institute for Behavioral Genetics Campus Box 447 University of Colorado, Boulder, CO 80309-0447 Telephone: (303) 735-2428 Fax: (303) 492-8063 Email: victoria.cosgrove@colorado.edu

Generalized Anxiety Disorder (GAD) is a commonly occurring anxiety disorder with a lifetime prevalence rate of 4-7%. Early-onset GAD tends to be more chronic and have associations with anxious personality. The serotonergic system has long been implicated in the regulation of mood and anxiety. Specific research has targeted the serotonin transporter (5-HTT), which functions to stop serotonin=s synaptic action by aiding in its reuptake into the presynaptic membrane. 5-HTT has a 44 base-pair repeat element (5-HTTLPR) in the 5= region of the gene. Its polymorphism leads to long (L, 528bp) and short (S, 484 bp) alleles; S is dominant over L and has half its transcriptional activity. Recent research has demonstrated association between anxiety and the S allele, however the specific association between 5-HTTLPR and early-onset GAD in adolescents has not yet been examined. This study seeks to investigate the possible association of 5-HTTLPR variants to GAD symptom counts in adolescents in order to investigate the relationship of the polymorphism to early-onset GAD. Participants were 711 12-year-old children from the Colorado Longitudinal Twin Study (LTS). GAD symptom counts were derived from the Diagnostic Interview Schedule for Children (DISC-IV). Controlling for population stratification, a sibling-based methodology for estimating allelic association with quantitative traits was applied (D.W. Fulker, S.S. Cherny, P.C. Sham, J.K Hewitt, 1999, Am. J. Hum. Genet. 64, 259-267). No association was found between 5-HTTLPR and DISC-IV GAD symptom counts in adolescents. Although results did not support the hypothesis that the 5-HTTLPR contributes to early-onset GAD symptomatology, it remains a worthwhile target of investigation since its role in anxious and depressive disorders is still unclear.

François X. Coudéo, Claire Mignot5, Stanislas Lyonneto and Arnold Munnicho. Academic impairment is the most frequent complication of neurofibromatose type-1(NF1) in children;.

oDépartement de Génétique, Hôpital Necker-Enfants Malades, Paris, France, 5Centre de Pédiatrie * les Collines de Cuques +, Résidence les Collines de Cuques, 6 av. de l=Armée d=Afrique, 13100 Aix-en-Provence, ;Supported in part by a grant from Association * Neurofibromatoses et Recklinghausen +, 34 Vieux chemin de Grenade, 31700 Blagnac, France

Address : Centre de Pédiatrie * les Collines de Cuques +, Résidence les Collines de Cuques, 6 av. de l=Armée d=Afrique, 13100 Aix-en-Provence, Telephone : 0618421316 Fax : 0442230613 Email : francoisxavier.coude@club-internet.fr

Neurofibromatosis type-1 (NF1) is a common genetic disorder associated with a variety of medical complications, cognitive impairments, and behavioral problems. One hundred and sixteen patients with NF1 (62 males, 54 females; mean age 12.4 years, SD 2.3) were studied in terms of complications and learning impairment (one or more grade repetitions or school exclusions). Seventy of 116 patients had significant learning impairment. Classical complications were present in 53 patients including the three most frequent complications in children, namely severe scoliosis (19), plexiform neurofibroma (16) and precocious puberty (14). There was no sex predominance except for plexidorm neurofibroma (11 male versus 5 female). Learning impairment predominated in first grades and was significantly sex dependent. Academic impairment is the most frequent complication in NF1. Because diagnosis is often a crucial problem in young children with six or more isolated café-au-lait spots, early developmental and bevahioral assessments might constitute a crucial diagnosis tool for these at risk children.

Brian M. D’Onofrio¹ , Eric Turkheimer¹, Robert E. Emery¹, Hermine H. Maes², Judy Silberg², and Lindon J. Eaves². The association between marital instability and offspring substance-use and emotional problems: A children of twins.

¹ Psychology Department, University of Virginia, ² Virginia Institute for Psychiatric and Behavior Genetics, Virginia Commonwealth University, ³ The analyses were supported by grants from the National Institute of Mental Health (MH67300), William T. Grant Foundation, and John Templeton Foundation. Data collection was supported by Grants GM-30250, AG-04954, AA-06781, MH-40828, and HL-48148 from the National Institutes of Health and a gift from RJR Nabisco.

Address : Department of Psychology University of Virginia, PO Box 400400 Charlottesville, VA 22904-4400 Telephone: 434-982-4750 Fax: 434-982-4766 email: bmd8q@virginia.edu

Although the association between parental marital instability and psychological problems in young adults has been well documented, the developmental mechanisms responsible for the statistical relations have remained unclear. The current study utilized the children of twins design to explore whether genetic or shared environmental factors confound the intergenerational associations related to marital instability in a sample of twins and their offspring from Virginia and the American Association of Retired Persons. A univariate twin analysis indicated that genetic factors contributed to variation in marital instability. Comparisons of offspring from monozygotic and dizygotic twins discordant for divorce, while also statistically controlling for parental characteristics, suggested that environmental factors specifically related to marital instability are associated with higher levels of alcohol problems and risk of smoking in the offspring. These findings are consistent with a quasi-causal theory of the effects of divorce on children. In contrast, selection factors, including genetic confounds, accounted for the increased risk of emotional problems and depression in offspring from divorced families. The study illustrates that passive gene-environment correlation must be considered when studying family risk factors because erroneous conclusions would have been reached if the analyses only relied on traditional, statistical approaches (e.g. analysis of covariance).

Cindy M. de Frias^{1, 2}, Kristina Annerbrink³, Lars Westberg³, Elias Eriksson³, Rolf Adolfsson⁴, and Lars-Göran Nilsson^{1, 5}. COMT gene polymorphism is associated with cognitive functioning in adulthood and old age.

¹Department of Psychology, Stockholm University, Stockholm, Sweden, ²Division of Geriatric Epidemiology, Karolinska Institute, Stockholm, Sweden, ³Department of Pharmacology, Göteborg University, Göteborg, Sweden, ⁴Department of Clinical Psychiatry, Division of Psychiatry, Umeå University, Umeå, Sweden, ⁵Center for Advanced Study, Norwegian Academy of Science and Letters, Oslo, Norway.

Address: Department of Psychology, Stockholm University, 106 91 Stockholm, Sweden Telephone: +46 8 163915 Fax: +46 8 159342 Email: cdefrias@psychology.su.se

Variation in cognitive performance is to a large extent explained by genes. In the prefrontal cortex, the catechol O-methyltransferase (COMT) gene is essential in the metabolic degradation of dopamine, a neurotransmitter implicated in cognitive functions. The present study examined the effect of a polymorphism in the COMT gene on individual differences and changes in memory and executive functions in adulthood and old age. Tests assessing episodic and semantic memory and executive functions were administered to 286 men (initially aged 35-85 years) from a random sample of the population (i.e., the Betula prospective cohort study; L-G. Nilsson, R. Adolfsson, L. Bäckman, C. M. de Frias, B. Molander, and L. Nyberg, in press, Aging, Neuropsychol, and Cogn.) at two occasions followed over a 5-year period. Carriers of the Met/Met genotype (with low enzyme activity) performed better on episodic memory, semantic memory, visuospatial ability, and verbal fluency as compared to carriers of the Val allele (with higher enzyme activity). Division of episodic memory into its recall and recognition components showed that the difference was specific to episodic recall, not recognition tasks; an effect that was observed across three age groups (middle-age, young-old, and old-old adults) and over a 5-year period. The COMT gene is a plausible candidate gene for cognitive functioning in adulthood and old age.

John C. DeFries¹ and Sally J. Wadsworth¹. Colorado Twin Study of Reading Disabilities²

¹Institute for Behavioral Genetics, University of Colorado, Boulder CO, USA, ²Supported by NICHD Center Grant HD-27802.

Address : Institute for Behavioral Genetics, University of Colorado, 447 UCB, Boulder CO 80309-0447 Telephone: 303 492 2839 Fax: 303 492 8063 Email: John.DeFries@Colorado.EDU

A major goal of the Colorado Learning Disabilities Research Center is to assess the genetic and environmental etiologies of reading deficits, Attention-Deficit/Hyperactivity Disorder (ADHD), and their comorbidity. To accomplish this goal, twin pairs are systematically ascertained from schools in Colorado and parental permission is sought to review the children=s school records. If either member of a pair manifests a school history of reading difficulties (e.g., low reading achievement test scores) or ADHD symptoms, both members of the pair are invited to complete an extensive test battery, including the Peabody Individual Achievement Test (PIAT). Employing discriminant weights estimated from an analysis of PIAT Reading Recognition, Reading Comprehension, and Spelling data, a discriminant function score is computed for each subject. Criteria for reading disability (RD) include being classified as affected by the discriminant score, having a verbal or performance IQ of at least 90, no evidence of neurological problems, and no uncorrected visual or auditory acuity deficits. As of November 30, 2003, 269 monozygotic and 216 same-sex dizygotic twin pairs have been ascertained in which at least one member of each pair meets these criteria. The probandwise concordance rates for RD in these twin pairs are 0.64 and 0.34, respectively (p = 1.05 H 10^-10). When the DeFries-Fulker basic regression model (J. C. DeFries and D.W. Fulker, 1985, Beh. Genet., 15, 467-473) was fitted to their discriminant function score data, h²_g = 0.57 (p = 1.67 H 10^-14), indicating that reading difficulties are due substantially to genetic influences. Results regarding the differential etiology of RD as a function of gender, comorbid RD and ADHD, bivariate linkage analyses for RD and ADHD symptoms, and association and candidate-gene analyses obtained from this and other ongoing studies will also be presented at the 2004 BGA symposium, AGenetics of Reading Disabilities.@

Ester M. Derks¹, J.J. Hudziak², C.E.M. Beijsterveldt¹, and D.I. Boomsma, D.I¹. Genetic analyses of Teacher Ratings on Aggression, Attention Problems and Anxiety in 7-, 10-, and 12-year-old children^3.

¹Department of Biological Psychology, Vrije Universiteit, Amsterdam, The Netherlands, ²Department of Psychiatry and Medicine (Division of Human Genetics), Center for Children, Youth and Families, and University of Vermont, College of Medicine, Burlington, USA, ³This work was supported by NWO Grant numbers 575-25-006, 575-25-012, and 904-57-94 (Boomsma, P.I.), and by NIMH Grant number MH58799 (Hudziak, P.I.)

Address: Vrije Universiteit Department of biological psychology van der Boechorststraat 1 1081 BT Amsterdam The Netherlands Telephone: 0031(0)20-4448743 Fax: 0031(0)20-4448832 Email: em.derks@psy.vu.nl

Parental ratings have shown large additive genetic, and moderate non-shared environmental influences on Attention Problems (AP), Aggression (AGG), and Anxiety (ANX). Shared environmental influences were present in AGG and ANX, and non-additive genetic influences were present in AP. (M.J.H. Rietveld, J.J. Hudziak, M. Bartels, C.E.M. Van Beijsterveldt, and D.I. Boomsma, 2004, Journal of Child Psychology and Psychiatry, 45, 577-588), and (J.J. Hudziak, C.E.M. van Beijsterveldt, M. Bartels, M.J.H. Rietveld, D.C. Rettew, E.M. Derks, and D.I. Boomsma, 2003, Behavior Genetics, 33, 575-589). The goal of this study is to determine how these findings might differ when using teacher reports. Objective : Perform univariate genetic analyses on teacher ratings of AP, AGG, and ANX in 7-, 10-, and 12-year-old boys and girls. Methods: Teachers completed the TRF at age 7 (N=1184 pairs), 10 (N=1055 pairs), and 12 (N=807 pairs). The current data do not yet show overlap between ages, therefore cross-sectional analyses were performed. Results: Individual differences in AP, AGG, and ANX in boys and girls were mainly explained by additive genetic factors. Non-shared environment contributed moderately to the variation in these syndromes. Non-additive genetic effects influenced variation in AGG, but only in 10-year-old girls. Influences of shared environment were significant on AGG, and AP in 12-year-old girls. Conclusions: Like parental ratings, teacher ratings of AP, AGG, and ANX in children are mainly explained by large genetic contributions and moderate non-shared environmental influences. Unlike parental ratings, no non-additive genetic influences were found on AP, and no shared environmental influences were found on ANX, although this latter finding may have been due to a lack of power. In addition, non-additive genetic influences were found on AGG in 10-year-old girls. In conclusion, estimates of genetic and environmental influences vary according to who provides the information (mother, father or teacher). However, regardless of informant, genetic influences are the most important contributors to individual differences in expression of psychopathology.

Danielle M. Dick¹, Howard J. Edenberg², Tatiana Foroud², Alison Goate¹, Laura Bierut¹, Bernice Porjesz³, & Henri Begleiter³. Identifying Genes Influencing Alcohol Dependence in the Collaborative Study on the Genetics of Alcoholism (COGA) Sample⁴.

¹ Washington University, St. Louis, MO USA, ² Indiana University School of Medicine, Indianapolis, IN USA, ³State University of New York, Brooklyn, NY USA, ⁴COGA is supported by the NIH Grant U10AA08403 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA).

Address : Washington University School of Medicine, Department of Psychiatry, Box 8134, 660 South Euclid, St. Louis, MO 63110. Telephone: 314-362-3999 Fax: 314-362-4247 E-mail: dickd@psychiatry.wustl.edu

The Collaborative Study on the Genetics of Alcoholism is a multi-center project with the goal of identifying genes influencing alcohol dependence. Families were ascertained through a proband in an inpatient or outpatient treatment center at one of six sites across the United States. Individuals completed a polydiagnostic interview, the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA), personality questionnaires, and an electrophysiological protocol. Data on 2282 individuals from 262 multiplex alcoholic families are available for genetic analyses. Linkage analyses were conducted on this sample to identify chromosomal regions potentially containing genes influencing alcohol dependence and related phenotypes and endophenotypes. Some of the strongest evidence of linkage (lod=5.0) was obtained for the beta 2 band of EEG on chromosome 4p (Porjesz et al., 2002, PNAS, 99, 3729-3733). There was also evidence of linkage to alcohol dependence diagnoses (lod=2.8) to a region of chromosome 4 just distal to these findings, and a bivariate analysis incorporating electrophysiological data increased the lod to 4.8 (Williams et al., 1999, AJHG, 65, 1148-1160). These linkage peaks corresponded to clusters of GABA-A receptor genes and ADH genes, respectively. These genes were considered strong candidates for potential involvement in alcohol dependence. We followed up these linkage findings by conducting family-based association analyses, testing multiple SNPs in each of the 4 GABA-A receptor genes and 7 ADH genes in the regions. We found significant evidence of association with one of the GABA-A receptor genes, GABRA2, and with one of the ADH genes, ADH4, with alcohol dependence. We have also used this strategy to identify genes that appear to influence the risk for alcohol dependence in several other chromosomal regions. We are hopeful that this new stage of high throughput association testing in the COGA sample will rapidly lead to the identification of additional genes contributing to the risk for alcohol dependence and related phenotypes.

Danielle M. Dick¹, Shaun Purcell², Richard J. Viken³, Jaakko Kaprio⁴, Lea Pulkkinen⁵, & Richard J. Rose³. Identifying Environmental Influences on Adolescent Substance Use in the Finnish Twin Studies⁶

¹ Washington University, St. Louis, MO USA, ² Whitehead Institute, Boston, MA USA, ³ Indiana University, Bloomington, IN USA, ⁴University of Helsinki, Finland, ⁵University of Jyvaskyla, Finland, ⁶The Finnish Twin Studies are supported by AA12502 from the NIAAA and by the Academy of Finland.

Address : Washington University School of Medicine, Department of Psychiatry, Box 8134 660 South Euclid, St. Louis, MO 63110, USA Telephone: 314-362-3999 Fax: 314-362-42