Biomedical subjects

M C Neale

Publications and source records attributed to M C Neale.

At least 55 records · Page 3Linked to original sources

PubMed1999

Evidence for genetic influences on human energy intake: results from a twin study using measured observations.

Human obesity is associated with greater-than-average energy intake, although relatively few studies have tested the heritability of food intake. The present study examined the genetic architecture of measured caloric intake during laboratory test meals in 36 monozygotic and 18 dizygotic twin pairs. A series of analyses tested the hypotheses that (1) there would be a genetic influence on total caloric intake, (2) there would be genes influencing total caloric intake above and beyond those influencing body composition, (3) there would be a phenotypic association between total caloric intake and fat mass above and beyond any genetic influences, and (4) there would be genetic influences on macronutrient intake (i.e., fat, carbohydrate, and protein intake) above and beyond total caloric intake. Results suggested genetic influences on age- and sex-adjusted total caloric intake (24-33% of the variance), although 95% confidence intervals were wide and suggested that "true" heritability estimates might be considerably lower or higher. Caloric intake was influenced by both common and unique environmental factors. Greater-than-average caloric intake was associated with increased adiposity, despite probable genetic influences on both phenotypes. Finally, there was evidence for macronutrient-specific familial influences, although the extent to which they were genetic or environmental in origin could not be teased apart. Results suggest that human obesity may be influenced by behaviors that are themselves genetically regulated. However, further studies are needed to obtain more precise heritability estimates and a better understanding of the conditions under which genetic influences on energy intake emerge.

Adult↗

PubMed1999

A note on the power provided by sibships of sizes 2, 3, and 4 in genetic covariance modeling of a codominant QTL.

The contribution of size 3 and size 4 sibships to power in covariance structure modeling of a codominant QTL is investigated. Power calculations are based on the noncentral chi-square distribution. Sixteen sets of parameter values are considered. Results indicate that size 3 and size 4 sibships provided large increases in power over size 2 sibships. On average a size 3 (4) sibship is 3 (6 to 7) times as informative as a size 2 sibship. The increase in power does not depend on the specific effects sizes of the independent variables in the model. These findings extend results presented by Fulker and Cherny (1996) and Schork (1993). We consider the informativeness of the size 2, 3, and 4 sibships, which differ in the unique configuration of IBD sharing. Three of the 10 size 3 and 7 of the 36 size 4 sibships are particularly informative. The results presented concern random (unselective) sampling but do have implications for selective sampling.

Alleles↗

PubMed1999

Possible confounds and their resolution in multivariate genetic analyses: comment on Bussell et al. (1999)

Assumptions behind the twin, sibling, and stepsibling design used in the Nonshared Environment in Adolescent Development study are considered. The D. A. Bussell et al. (1999) analyses of behavior in relationships indicate effects of both genetic and common-environment factors. Possible real and artifactual sources of the common environment include assortative mating, sibling interaction, failure of the equal environments assumption, and contaminated measures. Another potential source, specific to this study, is the effect of an individual in the mutual ratings of relationship with sibling, which would lead to a larger common-environment effect across variables than within variables. This alternative model did not indicate that there was a mutual rating effect. Univariate analyses confirm that the common-environment effect is present for both sibling and parent-child relationships. Most other potential sources of common environment, such as sibling interaction, do not account for the data.

Adolescent↗

PubMed1999

Susceptibility genes for nicotine dependence: a genome scan and followup in an independent sample suggest that regions on chromosomes 2, 4, 10, 16, 17 and 18 merit further study.

Cigarette smoking is associated with considerable morbidity, mortality, and public health costs. Genetic factors influence both smoking initiation and nicotine dependence, but none of the genes involved have been identified. A genome scan using 451 markers was conducted to identify chromosomal regions linked to nicotine dependence in a collection of 130 families containing 343 genotyped individuals (308 nicotine-dependent) from Christchurch, New Zealand. By pairwise analysis, the best result was with marker D2S1326 which gave a lod score under heterogeneity (H-LOD) of 2.63 (P=0.0012) and a nonparametric linkage (NPL, Zall) score of 2.65 (P=0.0011). To identify regions that warranted further study, rather than comparing the pairwise scores from the scan to theoretical thresholds, we compared them to an empirical baseline, found here to be H-LOD scores of 0.5 and Zall scores of 1.0. We also found a number of large (31-88 cM) regions where many (8-16) consecutive markers yielded small but positive Zall scores. Selected regions of chromosomes 2, 4, 10, 16, 17 and 18 were investigated further by additional genotyping of the Christchurch sample and an independent sample from Richmond, Virginia (91 families with 264 genotyped individuals, 211 nicotine-dependent). Multipoint nonparametric analysis showed the following maximums for the Christchurch sample: Chr. 2 (Zlr=2.61, P=0.005), Chr. 4 (Zlr=1.36, P=0.09), Chr. 10 (Zlr=2.43, P=0.008), Chr. 16 (Zlr=0.85, P=0.19), Chr. 17 (Zlr=1.64, P=0.05), Chr. 18 (Zlr=1.54, P=0.06). Analysis of the Richmond sample showed the following maximums: Chr. 2 (Zlr=1.00, P=0.15), Chr. 4 (Zlr=0.39, P=0.34), Chr. 10 (Zlr=1.21, P=0.11), Chr. 16 (Zlr=1.11, P=0.13), Chr. 17 (Zlr=1.60, P=0.05), Chr. 18 (Zlr=1.33, P=0.09). It is probable that the small samples used here provided only limited power to detect linkage. It may have been difficult therefore to detect genes of small effect, or those that are influencing risk in only a small proportion of the families. When simply judged against the usual standards of linkage significance, none of the individual regions yielded strong evidence in either sample. Some or all of the most positive results in the genome scan of the Christchurch sample, therefore, could be due to chance. However, the presence in the Christchurch scan of multiple large regions containing many consecutive positive markers, coupled with the relatively positive results in these same regions in the Richmond sample, suggests that some of these regions may contain genes influencing nicotine dependence and therefore deserve further study.

Adult↗

PubMed1999

A simulation study of the effects of assignment of prior identity-by-descent probabilities to unselected sib pairs, in covariance-structure modeling of a quantitative-trait locus.

Sib pair-selection strategies, designed to identify the most informative sib pairs in order to detect a quantitative-trait locus (QTL), give rise to a missing-data problem in genetic covariance-structure modeling of QTL effects. After selection, phenotypic data are available for all sibs, but marker data-and, consequently, the identity-by-descent (IBD) probabilities-are available only in selected sib pairs. One possible solution to this missing-data problem is to assign prior IBD probabilities (i.e., expected values) to the unselected sib pairs. The effect of this assignment in genetic covariance-structure modeling is investigated in the present paper. Two maximum-likelihood approaches to estimation are considered, the pi-hat approach and the IBD-mixture approach. In the simulations, sample size, selection criteria, QTL-increaser allele frequency, and gene action are manipulated. The results indicate that the assignment of prior IBD probabilities results in serious estimation bias in the pi-hat approach. Bias is also present in the IBD-mixture approach, although here the bias is generally much smaller. The null distribution of the log-likelihood ratio (i.e., in absence of any QTL effect) does not follow the expected null distribution in the pi-hat approach after selection. In the IBD-mixture approach, the null distribution does agree with expectation.

Alleles↗

PubMed1999

Testing the robustness of the likelihood-ratio test in a variance-component quantitative-trait loci-mapping procedure.

Detection of linkage to genes for quantitative traits remains a challenging task. Recently, variance components (VC) techniques have emerged as among the more powerful of available methods. As often implemented, such techniques require assumptions about the phenotypic distribution. Usually, multivariate normality is assumed. However, several factors may lead to markedly nonnormal phenotypic data, including (a) the presence of a major gene (not necessarily linked to the markers under study), (b) some types of gene x environment interaction, (c) use of a dichotomous phenotype (i.e., affected vs. unaffected), (d) nonnormality of the population within-genotype (residual) distribution, and (e) selective (extreme) sampling. Using simulation, we have investigated, for sib-pair studies, the robustness of the likelihood-ratio test for a VC quantitative-trait locus-detection procedure to violations of normality that are due to these factors. Results showed (a) that some types of nonnormality, such as leptokurtosis, produced type I error rates in excess of the nominal, or alpha, levels whereas others did not; and (b) that the degree of type I error-rate inflation appears to be directly related to the residual sibling correlation. Potential solutions to this problem are discussed. Investigators contemplating use of this VC procedure are encouraged to provide evidence that their trait data are normally distributed, to employ a procedure that allows for nonnormal data, or to consider implementation of permutation tests.

Analysis of Variance↗

PubMed1999

A major quantitative-trait locus for mole density is linked to the familial melanoma gene CDKN2A: a maximum-likelihood combined linkage and association analysis in twins and their sibs.

Important risk factors for melanoma are densely clustered melanocytic nevi (common moles) and mutations in the p16 (CDKN2A) gene. Nevi may be subclassified as raised or flat. In our sample, raised nevi were 27% of the total, and the two kinds had a correlation of.33. Correlations for total-nevus count (TNC) in 153 MZ and 199 DZ twin pairs were.94 and.60, respectively, which are compatible with a very-high degree of genetic determination. We hypothesized that some of the genetic variance might be due to variation in the p16 gene. Analysis of linkage to a highly polymorphic marker (D9S942), located close to p16, detected quantitative-trait-loci (QTL) effects accounting for 27% of variance in TNC, rising to 33% if flat but not raised moles were considered. Total heritability was higher for raised (.69) than for flat (.42) moles, but QTL linkage was 0 for raised moles, whereas it accounted for 80% of the heritability of flat moles; additionally, family environment accounted for only 15% of variance in raised versus 46% in flat moles. These findings suggest that raised and flat nevi have very different etiologies. Longer alleles at D9S942 were associated with higher flat-mole counts, and a novel modification to a within-sibship association test showed that this association is genuine and not due to population stratification, although it accounts for only 1% of total variance. Since germline mutations in the exons of CDKN2A are rare, it is likely that variants in the noncoding regions of this gene, or in another gene nearby, are responsible for this major determinant of moliness and, hence, of melanoma risk.

Child↗

PubMed1999

Replication of linkage studies of complex traits: an examination of variation in location estimates.

In linkage studies, independent replication of positive findings is crucial in order to distinguish between true positives and false positives. Recently, the following question has arisen in linkage studies of complex traits: at what distance do we reject the hypothesis that two location estimates in a genomic region represent the same gene? Here we attempt to address this question. Sampling distributions for location estimates were constructed by computer simulation. The conditions for simulation were chosen to reflect features of "typical" complex traits, including incomplete penetrance, phenocopies, and genetic heterogeneity. Our findings, which bear on what is considered a replication in linkage studies of complex traits, suggest that, even with relatively large numbers of multiplex families, chance variation in the location estimate is substantial. In addition, we report evidence that, for the conditions studied here, the standard error of a location estimate is a function of the magnitude of the expected LOD score.

Chromosome Mapping↗

PubMed1999

Genetic and environmental risk factors in the aetiology of illicit drug initiation and subsequent misuse in women.

BACKGROUND: Subsequent to initial exposure to the use of a psychoactive substance, psychoactive substance use disorder (PSUD) may or may not develop. AIMS: To investigate the relationship between the risk factors for initiation and the subsequent misuse of psychoactive substances. METHOD: The lifetime history of illicit substance use and misuse was obtained by telephone interview with 1934 members of female-female twin pairs. We apply a novel model, which estimates the role of genetic and environmental risk factors that influence initiation and those specific to misuse, to three classes of illicit psychoactive substances. RESULTS: The individual-specific environment and family environment influenced the probability of initiation, but only individual-specific environment had an impact on the probability of subsequent misuse. Genetic factors which influence the risk of initiation and of misuse were identified. CONCLUSIONS: Aetiological factors that influence drug initiation and subsequent misuse are correlated but not identical. Family environment is an important determinant of risk for drug experimentation. Two classes of genetic risk factors act on the liability to PSUD: those that influence the probability of initiation and those that influence the risk of misuse.

Adult↗

PubMed1999

Frequency of church attendance in Australia and the United States: models of family resemblance.

Data on frequency of church attendance have been obtained from separate cohorts of twins and their families from the USA and Australia (29,063 and 20,714 individuals from 5670 and 5615 families, respectively). The United States sample displayed considerably higher frequency of attendance at church services. Sources of family resemblance for this trait also differed between the Australian and US data, but both indicated significant additive genetic and shared environment effects on church attendance, with minor contributions from twin environment, assortative mating and parent-offspring environmental transmission. Principal differences between the populations were in greater maternal environmental effects in the US sample, as opposed to paternal effects in the Australian sample, and smaller shared environment effects observed for both women and men in the US cohort.

Adult↗

PubMed1999

Religious attendance and frequency of alcohol use: same genes or same environments: a bivariate extended twin kinship model.

Religious attendance has been shown to correlate negatively with alcohol use. We investigated whether this relationship is driven by genetic or environmental factors. Data on frequency of church attendance and frequency of alcohol use were obtained from twins and their families in the Virginia 30,000 study. A comprehensive bivariate model of family resemblance was fitted to the data using Mx. This model is described in detail. Results indicate that genetic factors primarily account for the relationship between alcohol and church attendance in males, whilst shared environmental factors, including cultural transmission and genotype-environment covariance, are stronger determinants of this association in females.

Alcohol Drinking↗

PubMed1999

Tobacco, alcohol and drug use in eight- to sixteen-year-old twins: the Virginia Twin Study of Adolescent Behavioral Development.

OBJECTIVE: This study reports prevalences of lifetime and current alcohol, tobacco and drug use in adolescents; examines associations between substance use and a number of putative risk factors; and estimates the contribution of genetic, shared and unique environmental influences on substance use. METHOD: Substance use data were collected using the Child and Adolescent Psychiatric Assessment on a population sample of 1,412 male and female monozygotic and dizygotic twin pairs, aged 8 through 16, from the Virginia Twin Study of Adolescent Behavioral Development. RESULTS: Heritabilities were estimated to be 84% and 82% for liability to lifetime and current tobacco use, respectively. For alcohol use the role of genes and environment varied according to the context of reporting. Liability to lifetime alcohol use was estimated to be under environmental control, with 71% of the variation shared by members of a twin pair and 29% unique to individual twins. Lifetime alcohol use without the permission of a parent or guardian and current use of alcohol were predominantly explained by genetic factors (h2 = 72% and 74%). The role of genetic factors increased and that of unique environmental factors decreased with increasing severity of alcohol use. Lifetime use of any drug showed a heritability of 45%, with the shared environment accounting for 47% of the variation. Shared environmental factors explained most of the variation in marijuana use. CONCLUSIONS: Genetic factors explained a significant proportion of the variation in the use of tobacco, alcohol and other drugs. Shared environmental factors contributed significantly to lifetime alcohol use and other drug use.

Adolescent↗

PubMed1998

Genetic and environmental influences on drug use and abuse/dependence in male and female twins.

Twins were recruited through alcohol and drug treatment programs. With structural equation modeling, genetic and environmental estimates were obtained for use and DSM-III abuse/dependence of sedatives, opioids, cocaine, stimulants, and cannabis as well as any illicit drug. Analyses were conducted separately for males and females. Models included thresholds based on population prevalence of use or abuse/dependence and ever having been in treatment. Genetic influences were found for most measures. They were generally stronger for males than females and for clinical diagnoses of abuse/dependence compared to use. Common environmental influences played a greater role in use than abuse/dependence.

Adolescent↗

PubMed1998

Genetic analysis of diagnostic systems of alcoholism in males.

BACKGROUND: Research into genes involved in alcoholism could benefit from use of diagnostic systems most sensitive to detecting genetic influences. In this study, heritable influences were estimated in a single twin sample with commonly used criteria for alcoholism. METHODS: Male twin probands ascertained through alcohol and drug abuse treatment programs and their same-sex cotwins (54 monozygotic and 65 dizygotic pairs) were diagnosed independently by DSM-III (alcohol dependence and alcohol abuse and/or dependence), Feighner (probable and definite alcoholism), and Cloninger (type 1 and type 2 alcoholism) systems. Using univariate structural equation modeling, heritability was estimated for each diagnostic system. RESULTS: The highest heritability estimates were obtained for Feighner probable alcoholism (h2 = .63), Cloninger type 2 alcoholism (h2 = .54), and DSM-III alcohol dependence (h2 = .52). CONCLUSIONS: Certain diagnostic systems appear to have greater sensitivity for detecting genetic influence and may therefore be more appropriate for use in molecular genetic studies attempting to find genes for alcoholism.

Adolescent↗

PubMed1998

Reliability of a lifetime history of major depression: implications for heritability and co-morbidity.

BACKGROUND: In unselected samples, the diagnosis of major depression (MD) is not highly reliable. It is not known if occasion-specific influences on reliability index familial risk factors for MD, or how reliability is associated with risk for co-morbid anxiety disorders. METHODS: An unselected sample of 847 female twin pairs was interviewed twice, 5 years apart, about their lifetime history (LTH) of MD, generalized anxiety disorder (GAD) and panic disorder (PD). Familial influences on reliability were examined using structural equation models. Logistic regression was used to identify clinical features that predict reliable diagnosis. Co-morbidity was characterized using the continuation ratio test. RESULTS: The reliability of a LTH of MD over 5 years was fair (kappa = 0.43). There was no evidence for occasion-specific familial influences on reliability, and heritability of reliably diagnosed MD was estimated at 66%. Subjects with unreliably diagnosed MD reported fewer symptoms and, if diagnosed with MD only at the first interview, less impairment and help seeking, or, if diagnosed with MD only at the second interview, fewer episodes and a longer illness. A history of co-morbid GAD or PD is more prevalent among subjects with reliably diagnosed MD. CONCLUSIONS: A diagnosis of MD based on a single psychiatric interview incorporates a substantial amount of measurement error but there is no evidence that transient influences on recall and diagnosis index familial risk for MD. Quantitative indices of risk for MD based on multiple interviews should reflect both the characteristics of MD and the temporal order of positive diagnoses.

Anxiety Disorders↗

PubMed1998

Assortative mating for major psychiatric diagnoses in two population-based samples.

BACKGROUND: Previous studies on assortment for psychiatric disorders have reported discrepant findings. We aimed to test whether there is a significant association for psychiatric diagnoses, including alcoholism, generalized anxiety disorder, major depressive disorder, panic disorder and phobias between husbands and wives in two population-based samples. We further evaluated whether marital resemblance occurs primarily within or across psychiatric disorders and if assortment for psychopathology is primary or secondary to assortment for correlated variables. METHODS: A model for mate selection addressed whether the correlation between mates for psychiatric disorders arises from direct assortment (primary homogamy) or through correlation with other variables for which assortment occurs (secondary homogamy) or through cross-variable assortment. The model accounted for within-person co-morbidity as well as across-spouse data. RESULTS: Findings suggested that a moderate degree of assortment exists both within and across psychiatric diagnoses. Only a small amount of the observed marital resemblance for mental illness could be explained by assortment for correlated variables such as age, religious attendance and education. Similar results were obtained for the two samples separately and confirmed in their joint analysis, revealing that the co-morbidity and assortment findings, except for the marital correlation for age, religious attendance and education, replicate across samples. CONCLUSIONS: Significant but moderate primary assortment exists for psychiatric disorders. The bias in twin studies that have ignored the small amount of assortment is negligible.

Adolescent↗

PubMed1998

Longitudinal genetic analysis of problem behaviors in biologically related and unrelated adoptees.

The genetic and environmental influences on problem behaviors at two assessment points, three years apart, and their stability were studied in a sample of international adoptees, initially aged 10 to 15 years. Parents of 111 pairs of adopted biological siblings, 221 pairs of adopted nonbiological siblings and 1484 adopted singletons completed the Child Behavior Checklist (75 pairs, 154 pairs and 1080 singletons respectively at second assessment). At first assessment, genetic factors accounted for more than 50% of the variance in the Externalizing, Aggressive Behavior, Attention Problems and Social Problems scales. Shared environmental influences explained 40% of the variance in the Total Problem scale and less for all other scales. Nonshared environmental influences were most important for the Internalizing scale and its subscales, and for the Thought Problems and Delinquent Behavior scales. At the second assessment, genetic factors explained most of the variance in the Total Problem, Externalizing and Aggressive Behavior scales, while nonshared environmental influences explained most of the variance in all other scales. Shared environmental influences explained 33% of the variance in the Internalizing scale and less for the other scales. The stability of the Externalizing scale over time was caused mostly by genetic factors, while nonshared environmental factors mostly caused the stability of the Internalizing scale.

Adolescent↗

PubMed1998

Longitudinal population-based twin study of retrospectively reported premenstrual symptoms and lifetime major depression.

OBJECTIVE: While family and twin studies suggest that retrospectively reported premenstrual symptoms are heritable, these studies have not accounted for the unreliability of such measures. In addition, we know little about the relationship of the familial risk factors for premenstrual symptoms and major depression. METHOD: Lifetime major depression and premenstrual-related tiredness, sadness, and irritability were assessed twice over 6 years in 1,312 menstruating female twins ascertained from a population-based twin register. A twin-measurement model--which permits estimation of the etiologic roles of genetic and environmental factors with correction for errors of measurement or short-term temporal fluctuations--was applied to these data. RESULTS: A single premenstrual symptom factor was found that was moderately stable over time. The best-fitting twin-measurement model estimated the heritability of the stable component of premenstrual symptoms at 56% and showed no impact of family-environmental factors. A bivariate twin-measurement model estimated that the genetic and environmental risk factors for lifetime major depression contributed only modestly to the etiology of premenstrual syndrome. No evidence was found for significant biases in the twin method. CONCLUSIONS: Retrospectively reported premenstrual-related symptoms of depression and anxiety are moderately stable over time and, when correction is made for this level of stability, substantially heritable. The genetic and environmental risk factors for these premenstrual symptoms and lifetime major depression are not closely related.

Adult↗