A genetic study of the family environment in the transition to early adolescence.

The aim of this longitudinal sibling adoption study was to estimate genetic and environmental components of variance in parent- and child-reported measures of the family environment (parental negative affect, negative control, and achievement orientation). Participants included 85 adoptive and 106 nonadoptive sibling pairs from the Colorado Adoption Project. Parents and children completed annual assessments of the family environment when the children were 10, 11, and 12 years old, and genetic and environmental parameter estimates were derived. Genetic influences were found for parent-reported negativity and warmth and child-reported achievement orientation, suggesting child genetic effects on these measures of the family environment. Shared environmental influences were found for parent-reported negativity, inconsistent discipline, warmth, and child-reported positivity. Nonshared environmental variance was substantial for children's ratings, but modest for parents' ratings.

Personality dimensions and substance misuse: relationships in adolescents, mothers and fathers.

The research addressed the question of whether relationships exist between personality dimensions, antisocial behavior, and alcohol or other substance misuse (AOSM) in adolescents and in their fathers and mothers, who often also have histories of AOSM. One hundred male adolescents (mean age 15.8 years) entering a residential treatment center for youths with AOSM, their mothers (n = 88, mean age 39.4 years), their fathers (n = 36, mean age 44.9 years), and community controls (n = 100 adolescents, mean age 16.5 years; n = 96 mothers, mean age 43.8 years; n = 87 fathers, mean age 45.9 years) were recruited. All participants completed a personality questionnaire and were interviewed on several measures, including structured interviews for psychopathology and substance misuse. The findings indicated that novelty seeking (NS), one of the personality dimensions, was significantly correlated with substance misuse in adolescent probands, adolescent controls, and proband fathers and mothers, but not in control fathers and mothers. Regression analyses that included conduct disorder (CD) or antisocial personality disorder (APD) symptoms indicated that both NS and CD or APD symptoms made significant contributions to the prediction of substance misuse in treatment group probands and in their fathers and mothers. The findings further suggest that NS and antisocial behaviors contribute independently to substance misuse in severely impaired adolescents and their fathers, but not in their mothers.

High-resolution mapping of quantitative trait loci in outbred mice.

Screening the whole genome of a cross between two inbred animal strains has proved to be a powerful method for detecting genetic loci underlying quantitative behavioural traits, but the level of resolution offered by quantitative trait loci (QTL) mapping is still too coarse to permit molecular cloning of the genetic determinants. To achieve high-resolution mapping, we used an outbred stock of mice for which the entire genealogy is known. The heterogeneous stock (HS) was established 30 years ago from an eight-way cross of C57BL/6, BALB/c, RIII, AKR, DBA/2, I, A/J and C3H inbred mouse strains. At the time of the experiment reported here, the HS mice were at generation 58, theoretically offering at least a 30-fold increase in resolution for QTL mapping compared with a backcross or an F2 intercross. Using the HS mice we have mapped a QTL influencing a psychological trait in mice to a 0.8-cM interval on chromosome 1. This method allows simultaneous fine mapping of multiple QTLs, as shown by our report of a second QTL on chromosome 12. The high resolution possible with this approach makes QTLs accessible to positional cloning.

Quantitative-trait locus for specific language and reading deficits on chromosome 6p.

Reading disability (RD), or dyslexia, is a complex cognitive disorder manifested by difficulties in learning to read, in otherwise normal individuals. Individuals with RD manifest deficits in several reading and language skills. Previous research has suggested the existence of a quantitative-trait locus (QTL) for RD on the short arm of chromosome 6. In the present study, RD subjects' performance in several measures of word recognition and component skills of orthographic coding, phonological decoding, and phoneme awareness were individually subjected to QTL analysis, with a new sample of 126 sib pairs, by means of a multipoint mapping method and eight informative DNA markers on chromosome 6 (D6S461, D6S276, D6S105, D6S306, D6S258, D6S439, D6S291, and D6S1019). The results indicate significant linkage across a distance of at least 5 cM for deficits in orthographic (LOD = 3.10) and phonological (LOD = 2.42) skills, confirming previous findings.

Combined linkage and association sib-pair analysis for quantitative traits.

An extension to current maximum-likelihood variance-components procedures for mapping quantitative-trait loci in sib pairs that allows a simultaneous test of allelic association is proposed. The method involves modeling of the allelic means for a test of association, with simultaneous modeling of the sib-pair covariance structure for a test of linkage. By partitioning of the mean effect of a locus into between- and within-sibship components, the method controls for spurious associations due to population stratification and admixture. The power and efficacy of the method are illustrated through simulation of various models of both real and spurious association.

Multivariate path analysis of specific cognitive abilities data at 12 years of age in the Colorado Adoption Project.

A parent-offspring multivariate conditional path model was fitted to specific cognitive abilities data from the Colorado Adoption Project (CAP) when the offspring were 12 years of age. The sample included 175 adoptees, 175 sets of adoptive parents, 175 biological mothers, 34 biological fathers, and 209 nonadopted children and their parents. Consistent with results obtained from multivariate genetic analyses of CAP data obtained at earlier ages, the effects of familial environmental transmission on individual differences in specific cognitive abilities were not significant. Assuming complete isomorphism (i.e., that the genetic and environmental etiologies of individual differences are the same) between the child and the adult measures, the heritability estimates for verbal, spatial, perceptual speed, and visual memory were .26, .35, .38, and .53, respectively. Although the heritability estimate for visual memory is somewhat higher than those for verbal, spatial, and perceptual speed abilities, these estimates are not significantly different. These estimates are higher than those obtained when the adoptees and controls were 4 years old (Rice et al., 1986, 1989); thus, heritabilities of specific cognitive abilities may increase as a function of cognitive development. Alternatively, genetic stability from childhood to adulthood may be greater from 12 years than from 4 years, which would be interpreted as greater heritability by the CAP parent-offspring design. The genetic correlations among the four measures were substantial, ranging from .27 between verbal and spatial abilities to .78 between spatial ability and perceptual speed. However, differences among these correlations are not significant, suggesting that their covariation may be due to general cognitive ability. Finally, estimates of bivariate-heritability indicate that on average about half of the phenotypic correlations among the four specific cognitive ability measures are due to genetic effects.

Genotype-environment correlations in late childhood and early adolescence: antisocial behavioral problems and coercive parenting.

A key question for understanding the interplay between nature and nurture in development is the direction of effects in socialization. A longitudinal adoption design provides a unique opportunity to investigate this issue in terms of genotype-environment correlations for behavioral problems. As part of the Colorado Adoption Project, adopted children were classified as being at genetic risk (N = 38) or not at genetic risk (N = 50) for antisocial behavior based on their biological mothers' self-report history of antisocial behavior collected prior to the birth of the child. From age 7 through age 12, adoptive parents reported on the negative control, positive parenting, and inconsistent parenting they use in managing their child's behavior. Repeated measures analysis of variance indicated that children at genetic risk were consistently more likely to receive negative parenting from their adoptive parents than children not at genetic risk, indicating an evocative genotype-environment correlation. However, the findings also showed that most of the association between negative parenting and children's externalizing behavior was not explicable on the basis of an evocative gene-environment correlation and that an additional environmentally mediated parental effect on children's behavior was plausible.

Adoption results for self-reported personality: evidence for nonadditive genetic effects?

Twin studies consistently indicate moderate genetic influence on individual differences in personality as assessed using self-report questionnaires, with heritability estimates typically about 40%. In this first analysis of self-report personality data from the longitudinal Colorado Adoption Project, little evidence is found for additive genetic influence in parent-offspring and sibling adoption analyses based on a foundation sample of 245 adoptive families and 245 nonadoptive families with adopted and nonadopted children assessed yearly from 9 to 16 years. Although several factors might contribute to the discrepancy between twin and adoption results, we suggest that nonadditive genetic influence, which can be detected by twin studies but not by adoption studies, is a likely culprit. These findings have important implications for attempts to identify specific genes responsible for genetic influence on personality.

An adoption study of depressive symptoms in middle childhood.

Several twin studies of children and adolescents have found significant heritability of depressive symptoms. In contrast, the sole adoption study of biologically related and biologically unrelated adopted siblings found no evidence for genetic influence. The present study attempts to confirm these results in middle childhood using two adoption designs. The sample, from the Colorado Adoption Project, included 180 adopted children (77 with adoptive siblings) and their biological and adoptive mothers, and 227 nonadopted children (93 with biological siblings) and their mothers. Mothers reported their own neuroticism, and children's depressive symptoms were reported by the parents and by the children themselves. For both the sibling adoption and the parent-offspring designs heritability was negligible, shared environment modest, and non-shared environment substantial, irrespective of child gender. Although the power of the sibling data is low, the combined findings from the two designs suggest that genetic effects on depressive symptoms in childhood may be somewhat smaller than previously estimated in twin studies.

A family history and direct interview study of the familial aggregation of substance abuse: the adolescent substance abuse study.

The adolescent substance abuse (ASA) study collected information concerning drug use and psychopathology on male adolescent probands in treatment for substance abuse and also on matched control adolescents, as well as all available family members of both groups. Information was obtained through direct interview and the family history method of assessment. Both methods revealed greater alcohol and drug use, conduct disorder (CD) and antisocial personality disorder (ASP) in the relatives of treatment probands as compared with control relatives. These results suggest familial transmission, not only for alcohol abuse, but also for non-alcohol substance abuse. Familial transmission for CD and ASP is also evident for both male and female relatives, although the prevalence of these disorders is significantly greater in males than females.

Exploring the genetic and environmental etiology of high general cognitive ability in fourteen- to thirty-six-month-old twins.

Although numerous theories have attempted to explain the origins of high general cognitive ability (g), the genetic and environmental etiology of high g during infancy and early childhood has not previously been investigated. We report results of a twin study of high cognitive ability at 14, 20, 24, and 36 months using twins from the more than 600 children participating in the MacArthur Longitudinal Twin Study. High g groups were formed from the ninetieth percentile and above at each age, with IQ equivalent means at or above 126 across the ages. Results suggest increasing genetic influence and increasing genetic stability from 14 to 36 months using DeFries-Fulker multiple regression analyses. However, genetic influences are substantial when examining individuals who possess high g scores averaged across all 4 ages. These results suggest that, although high cognitive ability may be genetically influenced in early childhood, these influences differ in magnitude from 14 to 36 months.

Family variables in substance-misusing male adolescents: the importance of maternal disorder.

Selected family variables, especially maternal behaviors, were studied as predictors of alcohol and drug misuse in severely disturbed adolescent boys from largely father-absent homes. The families of 50 male youths (mean age 15.8 years) in a residential center for alcohol and substance misuse were compared with the families of a community control group (mean age 16.3 years). Within-subject group comparisons also were made. Family structure, interactive processes, maternal and paternal alcohol and substance use, and criminality were assessed through direct interview and/or self-report. The families of alcohol- and substance-misusing boys were markedly disadvantaged or impaired on numerous family structure, process, and substance-misusing behavioral variables in comparison with community controls. Within the alcohol- and substance-misusing group itself, family process variables, maternal alcohol symptoms, and maternal criminality differentiated boys with more vs. less severe drug-dependence symptoms. Maternal alcohol problems and criminality were more important than family process variables. Paternal alcohol or substance misuse or criminality did not differentiate proband symptom severity. We concluded that maternal alcohol symptoms and criminality differentiate severity of drug dependence in severely disturbed, substance-misusing adolescent males from largely father-absent homes. Maternal substance misuse should be evaluated carefully in adolescent substance abuse treatment settings.

Increase in power through multivariate analyses.

Power to detect genetic and environmental influences increases not only with sample size but also with the number of measurements through longitudinal and/or multivariate designs, if those measurements correlate with each other. Power simulations are presented for uni- through quadrivariate cases, with differing genetic and environmental parameters. Even though subject attrition is a problem for most longitudinal studies, the gain in power available may more than make up for this shortcoming in many situations. In terms of planning studies to examine genetic and environmental influences, power calculations should not only consider sample size but number of measurements on particular phenotypes and their intercorrelations.

Quantitative trait locus analysis of contextual fear conditioning in mice.

Family, twin and adoption studies provide evidence for a substantial genetic component underlying individual differences in general intelligence, specific cognitive abilities and susceptibility to psychopathologies related to fear-inducing events. Contextual fear conditioning, which is highly conserved across species, can serve as a model for elucidating genes that regulate individual differences in learning and emotion. In fear conditioning, an initially neutral stimulus, such as a tone or a particular environment (context), elicits a fear response after it has been paired with an aversive stimulus, such as shock. Two neural circuits have been implicated in fear conditioning. The fear component is regulated by amygdaloid pathways, while the contextual component is, at least in part, dependent on the hippocampus. C57BL/6J (B6) and DBA/2J (D2) mice differ in several types of complex learning. including contextual fear conditioning. A quantitative trait locus (QTL) analysis of contextual fear conditioning was performed in a B6/D2 F2 intercross population. Two QTLs for contextual conditioning (lod score > 4.3) were identified on chromosomes 10 and 16. QTLs for conditioning to the auditory cue (lod score > 4.3) were localized to chromosomes 1 and 10. Suggestive QTLs (lod score = 2.8-4.1) for contextual conditioning were detected on chromosomes 1, 2 and 3.

Exploring the genetic etiology of low general cognitive ability from 14 to 36 months.

The genetic and environmental etiology of low general cognitive ability (g) during infancy and early childhood has not previously been investigated. The current study examined the genetic etiology of low cognitive ability at 14, 20, 24, and 36 months with twins from the MacArthur Longitudinal Twin Study. Low g groups were formed from the lowest 10th percentile at each age. Univariate probandwise concordance rates and DeFries-Fulker (J. C. DeFries & D. W. Fulker, 1985, 1988) multiple regression techniques suggest genetic etiology in low general cognitive ability groups. The stability of low general cognitive ability over time also appears to be primarily due to genetic factors. Although replication is necessary, these results suggest that the genetic etiology of low g during infancy and early childhood is at least as great as the heritability of g in the unselected population.

The familial aggregation of depressive symptoms, antisocial behavior, and alcohol abuse.

This study describes results from an ongoing family study of adolescent boys and their families designed to investigate potential risk factors for substance abuse. The adolescent treatment probands have severe drug and alcohol related problems and were recruited through a residential rehabilitation program. To date, the sample includes 251 individuals: 39 male probands and their families and 34 control families matched for age and geographic location (zip code). Probands and participating family members are given a structured interview which assesses alcohol and drug problems, and various psychiatric symptoms. The purpose of the present study was to examine the coaggregation of depressive symptoms, antisocial behavior, and alcohol misuse. Multivariate pedigree analyses were performed using a model that allowed for the estimation of vertical familial transmission, residual sibling resemblance, and assortative mating. Spouse correlations were estimated at .57, .21, and .31 for antisocial behavior, depressive symptoms, and alcohol abuse, respectively. Residual sibling environment (i.e., sibling resemblance unaccounted for by parent-offspring transmission) was not found for alcohol problem symptoms, but did contribute to resemblance for antisocial behavior and depressive symptoms. The proportion of variance accounted for by vertical familial transmission was estimated at approximately 30 to 40%. More important, correlations among the transmissible family factors for these psychiatric syndromes ranged from .58 to .73, suggesting substantial overlap among the underlying familial antecedents for these disorders.

An improved multipoint sib-pair analysis of quantitative traits.

Kruglyak and Lander (1995) recently published a multipoint sib-pair procedure based on the expected distribution of zero, one and two marker alleles shared identical by descent (ibd) and the method of maximum-likelihood (ML). Their approach uses phenotypic sib-pair differences, which ignores the bivariate structure of sib-pair data. Their simulations suggested that their method was more powerful than the regression method of Haseman and Elston (1972). We show through computation and simulation that their approach can be made more powerful still if the bivariate nature of sib-pair data is acknowledged. In addition, methods based on the average number of shared alleles that also employ bivariate ML procedures (Nance and Neale, 1989; Xu and Atchley, 1995) are more powerful than the approach they recommend and very similar to true ML using the distribution of ibd. The simple ML approach using the average number of shared alleles that we recommend seems to offer both optimal power and flexibility.

Quantitative trait loci for ethanol sensitivity in the LS x SS recombinant inbred strains: interval mapping.

We are mapping the genes (quantitative trait loci or QTLs) that are responsible for individual differences in ethanol sensitivity, measured as the duration of loss of righting, reflex (LORR) and blood ethanol concentrations upon recovery of the righting reflex (BEC). The Long-Sleep (LS) and Short-Sleep (SS) selected lines of mice manifest an 18-fold difference in LORR and serve as a rodent model for ethanol sensitivity. The LS x SS recombinant inbred (RI) series, developed from LS and SS lines, are an important resource for QTL mapping of ethanol-related responses. The current report summarizes the initial QTL analysis of LORR and BEC in the LS x SS strains and compares the results of correlational analysis with an interval-mapping approach. The data provide strong evidence for QTLs that influence ethanol sensitivity on mouse chromosomes 1 and 2 and possible QTLs on chromosomes 1, 3, 4, 5, 6, 7, 12, 13, 16, and 18. These results are compared to those from an F2 cross which confirms QTLs on chromosomes 1, 2, 4, and 18.

Quantitative trait locus analyses of sleep-times induced by sedative-hypnotics in LSXSS recombinant inbred strains of mice.

The long-sleep (LS) and short-sleep (SS) selected lines of mice show highly significant differences in sleep-time for many sedative-hypnotic drugs, and the quantitative genetic nature of these differences has been well-established. Using an interval-mapping approach, quantitative trait locus (QTL) analyses of LSXSS recombinant inbred (RI) strains have been applied to sleep-time responses for various classes of sedative-hypnotic drugs: alcohols (ethanol, n-propanol, and n-butanol), the atypical anesthetic chloral hydrate, barbiturates (pentobarbital and secobarbital), and benzodiazepines (chlordiazepoxide and flurazepam). Several provisional QTLs were mapped to similar locations within and between drug classes, suggesting that some common loci are involved in sleep-times elicited by these drugs. Consistent with correlations of strain mean sleep-times between drugs tested in the LSXSS recombinant inbred strains, the number of provisional QTLs mapping to the locations of highest significance for ethanol decreases when the lipid solubility of a particular drug becomes less similar to that of ethanol. Provisional QTLs mapped for the benzodiazepines, however, revealed considerable overlap with those mapped for ethanol, although these drugs represented the most lipid-soluble category of sedative-hypnotics tested. Provisional QTLs for pentobarbital and secobarbital differed from most of those mapped for the alcohols, which supports the hypothesis that alcohols and barbiturates exert their effects mainly through different biological mechanisms in the LS and SS lines. Blood ethanol concentrations at regaining the righting reflex also mapped to several provisional QTLs corresponding to ethanol-induced sleep-times that support the contention that sleep-time is a reasonable index of the observed differences in central nervous system sensitivities to ethanol between LS and SS mice.