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1.  Pleiotropic Effects of DCDC2 and DYX1C1 Genes on Language and Mathematics Traits in Nuclear Families of Developmental Dyslexia 
Behavior genetics  2010;41(1):67-76.
Converging evidence indicates that developmental problems in oral language and mathematics can predate or co-occur with developmental dyslexia (DD). Substantial genetic correlations have been found between language, mathematics and reading traits, independent of the method of sampling. We tested for association of variants of two DD susceptibility genes, DCDC2 and DYX1C1, in nuclear families ascertained through a proband with DD using concurrent measurements of language and mathematics in both probands and siblings by the Quantitative Transmission Disequilibrium Test. Evidence for significant associations was found between DCDC2 and ‘Numerical Facts’ (p value = 0.02, with 85 informative families, genetic effect = 0.57) and between ‘Mental Calculation’ and DYX1C1 markers −3GA (p value = 0.05, with 40 informative families, genetic effect = −0.67) and 1249GT (p value = 0.02, with 49 informative families, genetic effect = −0.65). No statistically significant associations were found between DCDC2 or DYX1C1 and language phenotypes. Both DCDC2 and DYX1C1 DD susceptibility genes appear to have a pleiotropic role on mathematics but not language phenotypes.
PMCID: PMC3939676  PMID: 21046216
Dyslexia; Association study; Pleiotropy; Mathematics; Language
2.  Comparison of Whole-Genome DNA Methylation Patterns in Whole Blood, Saliva, and Lymphoblastoid Cell Lines 
Behavior genetics  2012;43(2):168-176.
Epigenetic mechanisms, including DNA methylation, that underlie neuropsychiatric conditions have become a promising area of research. Most commonly used DNA sources in such studies are peripheral (whole) blood (WB), saliva (SL), and lymphoblastoid cell lines (LCLs); thus, the question of the consistency of DNA methylation patterns in those cells is of particular interest. To investigate this question we performed comparative analyses of methylation patterns in WB, SL, and LCLs derived from the same individuals, using Illumina HumanMethylation27 BeadChip arrays. Our results showed that DNA methylation patterns in SL are relatively consistent with those in WB, whereas the patterns in LCLs are similarly distinct from both WB and SL. The results indicated that due to multiple random and directed changes in DNA methylation throughout cell culturing, LCLs are not a reliable source of DNA for epigenetic studies and should be used with caution when investigating epigenetic mechanisms underlying biological processes.
PMCID: PMC3577999  PMID: 23269419
Lymphoblastoid cell lines; Saliva; Whole blood; DNA methylation; Methylation pattern
3.  Three Mutually Informative Ways to Understand the Genetic Relationships Among Behavioral Disinhibition, Alcohol Use, Drug Use, Nicotine Use/Dependence, and Their Co-occurrence: Twin Biometry, GCTA, and Genome-wide Scoring 
Behavior genetics  2013;43(2):97-107.
Behavioral Disinhibition is a trait hypothesized to represent a general vulnerability to the development of substance use disorders. We used a large community-representative sample (N = 7188) to investigate the genetic and environmental relationships among measures of Behavioral Disinhibition, Nicotine Use/Dependence, Alcohol Consumption, Alcohol Dependence, and Drug Use. First, using a subsample of twins (N = 2877), we used standard twin models to estimate the additive genetic, shared environmental, and non-shared environmental contributions to these five traits. Heritabilities ranged from .42–.58 and shared environmental effects ranged from .12–.24. Phenotypic correlations among the five traits were largely attributable to shared genetic effects. Second, we used Genome-wide Complex Trait Analysis (GCTA) to estimate as a random effect the aggregate genetic effect attributable to 515,384 common SNPs. The aggregated SNPs explained 10–30% of the variance in the traits. Third, a genome-wide scoring approach summed the actual SNPs, creating a SNP-based genetic risk score for each individual. After 10-fold internal cross-validation, the SNP sumscore correlated with the traits at .03 to .07 (p<.05), indicating small but detectable effects. SNP sumscores generated on one trait correlated at approximately the same magnitude with other traits, indicating detectable pleiotropic effects among these traits. Behavioral disinhibition thus shares genetic etiology with measures of substance use, and this relationship is detectable at the level of measured genomic variation.
PMCID: PMC3579160  PMID: 23362009
Behavioral Disinhibition; Alcohol; Drug; Tobacco; GWAS; Twins; Polygenetic
Behavior genetics  2013;43(2):151-160.
Conspecifics of many animal species physically compete to gain reproductive resources and thus fitness. Despite the importance of competitive ability across the animal kingdom, specific traits that influence or underpin competitive ability are poorly characterized. Here, we investigate whether there are genetic influences on competitive ability within male house mice. Additionally, we examined if litter demographics (litter size and litter sex ratio) influence competitive ability. We phenotyped two generations for a male s ability to possess a reproductive resource--a prime nesting site--using semi-natural enclosures with mixed sex groupings. We used the animal model coupled with an extensive pedigree to estimate several genetic parameters. Competitive ability was found to be highly heritable, but only displayed a moderate genetic correlation to body mass. Interestingly, litter sex ratio had a weak negative influence on competitive ability. Litter size had no significant influence on competitive ability. Our study also highlights how much remians unknown about the proximal causes of competitive ability.
PMCID: PMC3626107  PMID: 23291957
Heritability; Genetic Correlation; Life-History Evolution; Male-Male Competition; Sexual Selection
5.  A Demonstration of the Generalizability of Twin-based Research on Antisocial Behavior 
Behavior genetics  2012;43(2):120-131.
Researchers typically analyze samples of twin pairs in order to decompose trait variance into genetic and environmental components. This methodological technique, referred to as twin-based research, rests on several assumptions that must be satisfied in order to produce unbiased results. While research has analyzed the tenability of certain assumptions such as equal environments, less attention has been given to whether results gleaned from samples of twins generalize to the broader population of non-twins. The current study analyzed data drawn from the National Longitudinal Study of Adolescent Health and findings suggested twins do not systematically differ from the general population of non-twins on many measures of behavior and development. Furthermore, the effects of specific covariates on measures of antisocial behavior did not appear to differ across twin status. In sum, evidence concerning the etiology of antisocial behavior (e.g., heritability estimates) gleaned from twin-based research is likely to generalize to the non-twin population.
PMCID: PMC3683969  PMID: 23274656
twin research; assumptions; limitations; generalizability; external validity
6.  Common Genetic Variants Explain the Majority of the Correlation Between Height and Intelligence: The Generation Scotland Study 
Behavior Genetics  2014;44:91-96.
Greater height and higher intelligence test scores are predictors of better health outcomes. Here, we used molecular (single-nucleotide polymorphism) data to estimate the genetic correlation between height and general intelligence (g) in 6,815 unrelated subjects (median age 57, IQR 49–63) from the Generation Scotland: Scottish Family Health Study cohort. The phenotypic correlation between height and g was 0.16 (SE 0.01). The genetic correlation between height and g was 0.28 (SE 0.09) with a bivariate heritability estimate of 0.71. Understanding the molecular basis of the correlation between height and intelligence may help explain any shared role in determining health outcomes. This study identified a modest genetic correlation between height and intelligence with the majority of the phenotypic correlation being explained by shared genetic influences.
Electronic supplementary material
The online version of this article (doi:10.1007/s10519-014-9644-z) contains supplementary material, which is available to authorized users.
PMCID: PMC3938855  PMID: 24554214
Height; Intelligence; Molecular genetics; Genetic correlation; Generation Scotland
7.  Estimating Effect Sizes in Genome-Wide Association Studies 
Behavior genetics  2010;40(3):394-403.
Knowledge about the proportion of markers without effects (p0) and the effect sizes in large scale genetic studies is important to understand the basic properties of the data and for applications such as the control of false discoveries and designing adequately powered replication studies. Many p0 estimators have been proposed. However, high dimensional data sets typically comprise a large range of effect sizes and it is unclear whether the estimated p0 is related to the whole range, including markers with very small effects, or just the markers with large effects. In this article we develop an estimation procedure that can be used in all scenarios where the test statistic distribution under the alternative can be characterized by a single parameter (e.g. non-centrality parameter of the non-central chi-square or F distribution). The estimation procedure starts with estimating the largest effect in the data set, then the second largest effect, then the third largest effect, etc. We stop when the effect sizes become so small that they cannot be estimated precisely anymore for the given sample size. Once the individual effect sizes are estimated, they can be used to calculate an interpretable estimate of p0. Thus, our method results in both an interpretable estimate of p0 as well as estimates of the effect sizes present in the whole marker set by repeatedly estimating a single parameter. Simulations suggest that the effects are estimated precisely with only a small upward bias. The R codes that compute the effect estimates are freely downloadable from the website:
PMCID: PMC3923086  PMID: 20052610
Case–control designs; Effect size; False discoveries; Genomics; Multiple hypothesis testing; Proportion of true null hypotheses
8.  Moving closer to a public health model of language and learning disabilities: The role of genetics and the search for etiologies 
Behavior genetics  2011;41(1):1-5.
Continued progress in language and learning disabilities (LDs) research requires a renewed focused on issues of etiology. Genetics research forms a central tenet of such an agenda and is critical in clarifying relationships among oral language development, acquisition of literacy and mathematics, executive function skills, and comorbid conditions. For progress to be made, diversified efforts must continue to emphasize molecular and behavioral genetics (including quantitative genetics) approaches, in concert with multi-disciplinary and multi-modal projects, to provide an integrated understanding of the behavioral and biological manifestations of language and learning disabilities. Critically, increased efforts to include ethnic, socio-economic, and linguistic diverse participant samples across a range of developmental stages is required to meet the public health needs of learners in the US and across the world. Taken together, this body of work will continue to enhance our understanding of LDs and help us move toward a truly prevention based approach to language and learning disabilities.
PMCID: PMC3897164  PMID: 21229298
9.  Behavioral Characterization of a White-Throated Sparrow Homozygous for the ZAL2m Chromosomal Rearrangement 
Behavior genetics  2012;43(1):60-70.
The white-throated sparrow is rapidly becoming an important model in the genetics of social behavior because of a chromosomal rearrangement that segregates with a behavioral phenotype. Within a population, 50 % of individuals are heterozygous for a rearranged chromosome 2 (ZAL2m). These birds sing more and are more aggressive than the other 50 %, who lack the rearrangement. A disassortative mating system, in which heterozygotes almost never interbreed, ensures that ZAL2m/2m homozygotes are extremely rare. Here, we provide the first systematic characterization of such a homozygote, a hatch-year female. Her plumage was atypical of her age and sex, resembling that of an adult male. She was extremely vocal and aggressive, dominating her opponents in behavioral tests. Her phenotype was thus an exaggerated version of a typical ZAL2/2m heterozygote, supporting the hypothesis that alleles inside the ZAL2m rearrangement confer high aggression and further emphasizing this species’ value as a model of social behavior.
PMCID: PMC3552124  PMID: 23264208
Aggression; Alternative phenotypes; Chromosomal inversion; Life history strategies; Polymorphism; White-throated sparrow
10.  Prenatal rapamycin results in early and late behavioral abnormalities in wildtype C57Bl/6 mice 
Behavior genetics  2012;43(1):51-59.
Mammalian target of rapamycin (mTOR) signaling has been shown to be deregulated in a number of genetic, neurodevelopmental disorders including Tuberous Sclerosis Complex, Neurofibromatosis, Fragile X, and Rett syndromes. As a result, mTOR inhibitors, such as rapamycin and its analogs, offer potential therapeutic avenues for these disorders. Some of these disorders – such as Tuberous Sclerosis Complex – can be diagnosed prenatally. Thus, prenatal administration of these inhibitors could potentially prevent the development of the devastating symptoms associated with these disorders. To assess the possible detrimental effects of prenatal rapamycin treatment, we evaluated both early and late behavioral effects of a single rapamycin treatment at embryonic day 16.5 in wildtype C57Bl/6 mice. This treatment adversely impacted early developmental milestones as well as motor function in adult animals. Rapamycin also resulted in anxiety-like behaviors during both early development and adulthood but did not affect adult social behaviors. Together, these results indicate that a single, prenatal rapamycin treatment not only adversely affects early postnatal development but also results in long lasting negative effects, persisting into adulthood. These findings are of importance in considering prenatal administration of rapamycin and related drugs in the treatment of patients with neurogenetic, neurodevelopmental disorders.
PMCID: PMC3554236  PMID: 23229624
mTOR; tuberous sclerosis; embryonic; mouse
Behavior genetics  2012;43(1):85-96.
PMCID: PMC3573860  PMID: 23264207
12.  Substantial Genetic Overlap between Schizotypy and Neuroticism: A Twin Study 
Behavior genetics  2012;42(5):10.1007/s10519-012-9558-6.
Schizotypy is phenotypically associated with neuroticism. To reveal the origin of this association, we assessed 3349 (1449 monozygotic (MZ), 1105 dizygotic (DZ) same-sex and 795 DZ opposite-sex) twins on a 12-item version of Chapman’s Psychosis-Proneness Scales and the short-form of the Eysenck Personality Questionnaire-Revised as measures of schizotypy and neuroticism.
A substantial proportion (.51 with 95% CI from .38 to .64) of the phenotypic correlation of .37 between neuroticism and the perceptual and ideational components of schizotypy was accounted for by shared genetic influences on these two traits. Moreover, a Cholesky decomposition including anhedonia, hypomania and impulsivity fully accounted for the heritable variance in perceptual and ideational components of schizotypy.
These findings suggest a shared genetic etiology between neuroticism and perceptual and ideational components of schizotypy and affect future investigations on the etiology of these phenotypically overlapping traits and affective and psychotic disorders.
PMCID: PMC3816282  PMID: 22955548
Perceptual aberration; Magical ideation; Phenotypic correlation; Behavior genetics; Schizotypy; Neuroticism
13.  Lifestyle modifies the relationship between body composition and adrenergic receptor genetic polymorphisms, ADRB2, ADRB3 and ADRA2B: A secondary analysis of a randomized controlled trial of physical activity among postmenopausal women 
Behavior genetics  2010;40(5):10.1007/s10519-010-9361-1.
Genetic variations in the adrenergic receptor (ADR) have been associated with body composition in cross-sectional studies. Recent findings suggest that ADR variants may also modify body composition response to lifestyle. We assessed the role of ADR variants in body composition response to 12 months of resistance training versus control in previously sedentary postmenopausal women. Randomized trial completers were genotyped for A2BGlu9/12 by fragment length analysis, and B2Gln27Glu and B3Trp64Arg by TaqMan (n=148, 54% hormone therapy users). Associations between genotypes and body composition, by dual energy X-ray absorptiometry, were analyzed using univariate models. There was no main effect of individual genes on change in body composition, however, gene × exercise interactions were observed for A2BGlu9/12 and B2Gln27Glu on change in lean soft tissue (LST, p=0.02); exercisers on the A2BGlu9- background gained LST compared to a loss among controls over 12 months (p<0.05), with no significant intervention effect on the A2B Glu9+ background. Similarly, there was a significant LST gain with exercise on the B2Glu27+ background compared to loss among controls and no intervention effect on the B2Glu27- background. A non-significant association between total body fat (TBF) and B3Trp64Arg persisted among sedentary controls only when intervention groups were separated (%TBF gain with B3Arg 64+ carriage, p=0.03); exercisers lost TBF regardless of genotype. In summary, effect modification by lifestyle was demonstrated on ADR A2B, B2, and B3 genetic backgrounds. Individuals with certain ADR genotypes may be more vulnerable to adverse changes in body composition with sedentary behavior, thus these candidate genes warrant further study.
PMCID: PMC3817010  PMID: 20401689
body composition; lean soft tissue; resistance training; adrenergic receptor; post-menopausal women; genetics
14.  Genetic and Environmental Transmission of Body Mass Index Fluctuation 
Behavior genetics  2012;42(6):867-874.
This study sought to determine the relationship between BMI fluctuation and cardiovascular disease phenotypes, diabetes, and depression and the role of genetic and environmental factors in individual differences in BMI fluctuation using the extended twin-family model (ETFM).
Study Design and Methods
This study included 14,763 twins and their relatives. Health and Lifestyle Questionnaires were obtained from 28,492 individuals from the Virginia 30,000 dataset including twins, parents, siblings, spouses, and children of twins. Self-report cardiovascular disease, diabetes, and depression data were available. From self-reported height and weight, BMI fluctuation was calculated as the difference between highest and lowest BMI after age 18, for individuals 18–80 years. Logistic regression analyses were used to determine the relationship between BMI fluctuation and disease status. The ETFM was used to estimate the significance and contribution of genetic and environmental factors, cultural transmission, and assortative mating components to BMI fluctuation, while controlling for age. We tested sex differences in additive and dominant genetic effects, parental, non-parental, twin, and unique environmental effects.
BMI fluctuation was highly associated with disease status, independent of BMI. Genetic effects accounted for ~34% of variance in BMI fluctuation in males and ~43% of variance in females. The majority of the variance was accounted for by environmental factors, about a third of which were shared among twins. Assortative mating, and cultural transmission accounted for only a small proportion of variance in this phenotype.
Since there are substantial health risks associated with BMI fluctuation and environmental components of BMI fluctuation account for over 60% of variance in males and over 50% of variance in females, environmental risk factors may be appropriate targets to reduce BMI fluctuation.
PMCID: PMC3474545  PMID: 23011216
BMI; Chronic Disease; Weight change; Heritability; Family Studies
15.  Adjusted Confidence Intervals for a Bounded Parameter 
Behavior genetics  2012;42(6):886-898.
It is well known that the regular likelihood ratio test of a bounded parameter is not valid if the boundary value is being tested. This is the case for testing the null value of a scalar variance component. Although an adjusted test of variance component has been suggested to account for the effect of its lower bound of zero, no adjustment of its interval estimate has ever been proposed. If left unadjusted, the confidence interval of the variance may still contain zero when the adjusted test rejects the null hypothesis of a zero variance, leading to conflicting conclusions. In this research, we propose two ways to adjust the confidence interval of a parameter subject to a lower bound, one based on the Wald test and the other on the likelihood ratio test. Both are compatible to the adjusted test and parametrization-invariant. A simulation study and two examples are given in the framework of ACDE models in twin studies.
PMCID: PMC3486787  PMID: 22971875
confidence interval; variance component; likelihood ratio test; Wald test; ACDE models
16.  Gene Expression in Aminergic and Peptidergic Cells During Aggression and Defeat: Relevance to Violence, Depression and Drug Abuse 
Behavior genetics  2011;41(6):10.1007/s10519-011-9462-5.
In this review, we examine how experiences in social confrontations alter gene expression in mesocorticolimbic cells. The focus is on the target of attack and threat due to the prominent role of social defeat stress in the study of coping mechanisms and victimization. The initial operational definition of the socially defeated mouse by Ginsburg and Allee (1942) enabled the characterization of key endocrine, cardiovascular, and metabolic events during the initial response to an aggressive opponent and during the ensuing adaptations. Brief episodes of social defeat stress induce an augmented response to stimulant challenge as reflected by increased locomotion and increased extracellular dopamine (DA) in the nucleus accumbens (NAC). Cells in the ventral tegmental area (VTA) that project to the NAC were more active as indicated by increased expression of c-fos and Fos-immunoreactivity and BDNF. Intermittent episodes of social defeat stress result in increased mRNA for MOR in brainstem and limbic structures. These behavioral and neurobiological indices of sensitization persist for several months after the stress experience. The episodically defeated rats also self-administered intravenous cocaine during continuous access for 24 h (“binge”). By contrast, continuous social stress, particularly in the form of social subordination stress, leads to reduced appetite, compromised endocrine activities, and cardiovascular and metabolic abnormalities, and prefer sweets less as index of anhedonia. Cocaine challenges in subordinate rats result in a blunted psychomotor stimulant response and a reduced DA release in NAC. Subordinate rats self-administer cocaine less during continuous access conditions. These contrasting patterns of social stress result from continuous vs. intermittent exposure to social stress, suggesting divergent neuroadaptations for increased vulnerability to cocaine self-administration vs. deteriorated reward mechanisms characteristic of depressive-like profiles.
PMCID: PMC3806208  PMID: 21416141
Social stress; Defeat; Ventral tegmental area; Dorsal raphe; Amphetamine; Cocaine; Sensitization; Tolerance; Anhedonia
17.  Strain-dependent Effects of Acute, Chronic, and Withdrawal from Chronic Nicotine on Fear Conditioning 
Behavior genetics  2011;42(1):133-150.
The effects of nicotine on cognitive processes such as learning and memory may play an important role in the addictive liability of tobacco. However, it remains unknown whether genetic variability modulates the effects of nicotine on learning and memory. The present study characterized the effects of acute, chronic, and withdrawal from chronic nicotine administration on fear conditioning, somatic signs, and the elevated plus maze in 8 strains of inbred mice. Strain-dependent effects of acute nicotine and nicotine withdrawal on contextual fear conditioning, somatic signs, and the elevated plus maze were observed, but no association between the effects of acute nicotine and nicotine withdrawal on contextual fear conditioning were observed, suggesting that different genetic substrates may mediate these effects. The identification of genetic factors that may alter the effects of nicotine on cognition may lead to more efficacious treatments for nicotine addiction.
PMCID: PMC3788685  PMID: 21822688
Nicotine; Genetics; Addiction; Anxiety; Learning; Withdrawal
18.  Lineage is an Epigenetic Modifier of QTL Influencing Behavioral Coping with Stress 
Behavior genetics  2005;35(2):189-198.
A genome-wide scan was carried out on a segregating F2 population of rats derived from reciprocal intercrosses between two inbred strains of rats, Fisher 344 (F344) and Wistar Kyoto (WKY) that differ significantly in their behavioral coping responses to stress measured by the defensive burying (DB) test. The DB test measures differences in coping strategies by assaying an animal’s behavioral response to an immediate threat. We have previously identified three X-linked loci contributing to the phenotypic variance in behavioral coping. Here we report on six significant autosomal quantitative trait loci (QTL) related to different behaviors in the DB test:one for the number of shocks received, three for number of prod approaches, one for latency to bury, and one pleiotropic locus affecting both approach and latency. These QTL contributing to different aspects of coping behaviors show that the effect of genotype on phenotype is highly dependent on lineage. The WKY lineage was particularly influential, with five out of the six QTL affecting coping behavior only in rats of the WKY lineage, and one locus affecting only those in the F344 lineage. Thus, epigenetic factors, primarily of WKY origin, may significantly modulate the genetic contribution to variance in behavioral responses to stress in the DB test.
PMCID: PMC3764451  PMID: 15685431
Coping; defensive burying; epigenetic; lineage; linear modeling; QTL; stress
19.  Additional Evidence against Shared Environmental Contributions to Attention-Deficit/Hyperactivity Problems 
Behavior genetics  2012;42(5):711-721.
A recent meta-analysis (Burt, 2009) indicated that shared environmental influences (C) do not contribute to Attention-Deficit/Hyperactivity Disorder (ADHD). Unfortunately, the meta-analysis relied almost exclusively on classical twin studies. Although useful in many ways, some of the assumptions of the classical twin model (e.g., dominant genetic and shared environmental influences do not simultaneously influence the phenotype) can artifactually decrease estimates of C. There is thus a need to confirm that dominant genetic influences are not suppressing estimates of C on ADHD. The current study sought to do just this via the use of a nuclear twin family model, which allows researchers to simultaneously model and estimate dominant genetic and shared environmental influences. We examined two independent samples of child twins: 312 pairs from the Michigan State University Twin Registry (MSUTR) and 854 pairs from the PrEschool Twin Study in Sweden (PETSS). Shared environmental influences were found to be statistically indistinguishable from zero and accounted for less than 5% of the variance. We conclude that the presence of dominant genetic influences does not account for the absence of C on ADHD.
PMCID: PMC3440545  PMID: 22566176
ADHD; nuclear twin family model; shared environment; genetic influences
20.  The Magnitude of Genetic and Environmental Influences on Parental and Observational Measures of Behavioral Inhibition and Shyness in Toddlerhood 
Behavior genetics  2012;42(5):764-777.
Behavioral inhibition is a temperamental trait that refers to slow approach to novel items, shyness towards new people, and fearfulness in new situations, and individuals may develop inhibited response styles by as early as two years of age. There are important methodological considerations in the assessment of early temperament, with parental report and observational measures providing both corroborative and unique data. The present study examined behavioral inhibition measured by parental report and observational measures in a genetically informative sample to delineate the agreement between the methods and the uniqueness of each method, and to estimate the magnitude of genetic and environmental influences on the common and unique variance. The biometric, psychometric, and rater bias models were conducted to study the covariance between measurement modalities. Overall, the results suggested a common phenotype was assessed by both parents and observers. The latent phenotype underlying parental and observational measures of behavioral inhibition was moderately to substantially heritable.
PMCID: PMC3443291  PMID: 22806186
temperament; behavioral inhibition; rater bias; toddler; shyness; twin study methods; parent report; observational measures
21.  Cognitive Change in Older Women Using a Computerised Battery: A Longitudinal Quantitative Genetic Twin Study 
Behavior Genetics  2013;43:468-479.
Cognitive performance is known to change over age 45, especially processing speed. Studies to date indicate that change in performance with ageing is largely environmentally mediated, with little contribution from genetics. We estimated the heritability of a longitudinal battery of computerised cognitive tests including speed measures, using a classical twin design. 324 (127 MZ, 197 DZ) female twins, aged 43–73 at baseline testing, were followed-up after 10 years, using seven measures of the Cambridge Automated Neuropsychological Test battery, four of which were measures of response latency (speed). Results were analysed using univariate and bivariate structural equation modelling. Heritability of longitudinal change was found in 5 of the 7 tests, ranging from 21 to 41 %. The genetic aetiology was remarkably stable. The first principle component of change was strongly associated with age (p < 0.001) and heritable at 47 % (27–62 %). While estimates for heritability increased in all measures over time compared to baseline, these increases were statistically non-significant. This computerised battery showed significant heritability of age-related change in cognition. Focus on this form of change may aid the search for genetic pathways involved in normal and pre-morbid cognitive ageing.
Electronic supplementary material
The online version of this article (doi:10.1007/s10519-013-9612-z) contains supplementary material, which is available to authorized users.
PMCID: PMC3825151  PMID: 23990175
Processing speed; Heritability; Cognition; Aging; Twin study; Accelerating change
22.  Genetic and Environmental Variation in Lung Function Drives Subsequent Variation in Aging of Fluid Intelligence 
Behavior genetics  2013;43(4):274-285.
Longitudinal studies document an association of pulmonary function with cognitive function in middle-aged and older adults. Previous analyses have identified a genetic contribution to the relationship between pulmonary function with fluid intelligence. The goal of the current analysis was to apply the biometric dual change score model to consider the possibility of temporal dynamics underlying the genetic covariance between aging trajectories for pulmonary function and fluid intelligence. Longitudinal data from the Swedish Adoption/Twin Study of Aging were available from 808 twins ranging in age from 50 to 88 years at the first wave. Participants completed up to six assessments covering a 19-year period. Measures at each assessment included spatial and speed factors and pulmonary function. Model-fitting indicated that genetic variance for FEV1 was a leading indicator of variation in age changes for spatial and speed factors. Thus, these data indicate a genetic component to the directional relationship from decreased pulmonary function to decreased function of fluid intelligence.
PMCID: PMC3753107  PMID: 23760789
Pulmonary function; Cognitive function; Dual-change-score model; Longitudinal twin data; Statistical analysis; Aging; Health
23.  The CHRNA5/A3/B4 Gene Cluster and Tobacco, Alcohol, Cannabis, Inhalants and Other Substance Use Initiation: Replication and New Findings Using Mixture Analyses 
Behavior genetics  2012;42(4):636-646.
Multiple studies have provided evidence for genetic associations between single nucleotide polymorphisms (SNPs) located on the CHRNA5/A3/B4 gene cluster and various phenotypes related to Nicotine Dependence (Greenbaum et al. 2009). Only a few studies have investigated other substances of abuse. The current study has two aims, (1) to extend previous findings by focusing on associations between the CHRNA5/A3/B4 gene cluster and age of initiation of several different substances, and (2) to investigate heterogeneity in age of initiation across the different substances. All analyses were conducted with a subset of the Add Health study with available genetic data. The first aim was met by modeling onset of tobacco, alcohol, cannabis, inhalants, and other substance use using survival mixture analysis (SMA). Ten SNPs in CHRNA5/A3/B4 were used to predict phenotypic differences in the risk of onset, and differences between users and non-users. The survival models aim at investigating differences in the risk of initiation across the 5–18 age range for each phenotype separately. Significant or marginally significant genetic effects were found for all phenotypes. The genetic effects were mainly related to the risk of initiation and to a lesser extent to discriminating between users and non-users. To address the second goal, the survival analyses were complemented by a latent class analysis that modeled all phenotypes jointly. One of the ten SNPs was found to predict differences between the early and late onset classes. Taken together, our study provides evidence for a general role of the CHRNA5/A3/B4 gene cluster in substance use initiation that is not limited to nicotine and alcohol.
PMCID: PMC3743232  PMID: 22382757
Survival mixture analysis; Nicotine initiation; Substance use; CHRNA5/B3/A4 cluster
24.  Differences in Aggressive Behavior and DNA Copy Number Variants Between BALB/cJ and BALB/cByJ Substrains 
Behavior genetics  2009;40(2):201-210.
Some BALB/c substrains exhibit different levels of aggression. We compared aggression levels between male BALB/cJ and BALB/cByJ substrains using the resident intruder paradigm. These substrains were also assessed in other tests of emotionality and information processing including the open field, forced swim, fear conditioning, and prepulse inhibition tests. We also evaluated single nucleotide polymorphisms (SNPs) previously reported between these BALB/c substrains. Finally, we compared BALB/cJ and BALB/cByJ mice for genomic deletions or duplications, collectively termed copy number variants (CNVs), to identify candidate genes that might underlie the observed behavioral differences. BALB/cJ mice showed substantially higher aggression levels than BALB/cByJ mice; however, only minor differences in other behaviors were observed. None of the previously reported SNPs were verified. Eleven CNV regions were identified between the two BALB/c substrains. Our findings identify a robust difference in aggressive behavior between BALB/cJ and BALB/cByJ substrains, which could be the result of the identified CNVs.
PMCID: PMC3722062  PMID: 20033273
Aggression; Resident intruder; BALB/c; CNV; Substrain
25.  The D2 Dopamine Receptor Gene and Nicotine Dependence Among Bladder Cancer Patients and Controls 
Behavior genetics  2009;40(1):49-58.
Multiple twin, family, and genetic studies have rendered substantial evidence supporting an association between hereditary factors and smoking initiation and maintenance. To investigate further the relationships between the DRD2 genotypes, cigarette use and nicotine dependence, we examined the prevalence of polymorphisms in the TaqIA (A1 and A2) and the TaqIB (B1 and B2) alleles among a series of 608 non-Hispanic White bladder cancer patients and 608 matched controls. Among ever-smoking controls, A1 and B1 genotypes exhibited a greater smoking intensity and were significantly younger at the age of initiation than A2A2 or B2B2 genotypes (two-sided P < 0.05). Among former smoking cases, persons with the A1 genotypes exhibited significantly higher mean pack-years and years of smoking, and were younger at the age of initiation than were persons with the A2A2 genotype (two-sided P < 0.05). Additionally, current smokers with the A1 genotypes reported fewer quit attempts than those with the A2A2 genotype (two-sided P < 0.01). The present study suggests that the DRD2 alleles A1 and B1 confer greater vulnerability to tobacco use.
PMCID: PMC3719969  PMID: 19842028
DRD2; Bladder cancer; Nicotine dependence

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