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Congenital anomalies are a major cause of fetal and neonatal death and of childhood morbidity. Chromosomal and other genetic abnormalities, environmental teratogens and some nutritional deficiencies account for some congenital anomalies but the majority are of unknown etiology. The hypothesis is here proposed that a significant proportion of congenital anomalies and cerebral palsy of unknown etiology are attributable to a monozygotic multiple conception with monochorionic placentation and that these anomalies, even in singletons, may be explained by early, unrecognized or unrecorded loss of one conceptus in a monochorionic monozygotic conception. The pathological mechanism is hemodynamic instability with episodes of acute feto–fetal transfusion that produce ischemic organ impairment in either or both twins. The resultant clinical abnormality will depend on range of severity (fetal death, infant death, congenital anomaly, normal infant), site or combination of sites (which organ[s] present[s] with the congenital anomaly) and timing (early, middle or late in gestation as shown by variation in brain pathology that is observed).
Commentary on Cherkas et al. (2004). Genetic Influences on Female Infidelity and Number of Sexual Partners in Humans: A Linkage and Association Study on the Role of the Vasopressin Receptor Gene (AVPR1A). Twin Research, 7, 649–658.
Twin studies of complex traits, such as behavior or psychiatric diagnoses, frequently involve univariate analysis of a sum score derived from multiple items. In this article, we show that absence of measurement invariance across zygosity can bias estimates of genetic and environmental components of variance. Specifically, if the item responses are considered as multiple indicators of a latent factor, and the aim is to partition the variance in the latent factor, then the factor loadings relating the items to the factor should be equal for monozygotic (MZ) and dizygotic (DZ) twins. While it seems unlikely, a priori, that these loadings should differ as a function of zygosity, certain special measurement situations are cause for concern. Ratings by parents, or self-ratings of pheno- types which are more easily observed in others than via introspection, may be tainted by the co-twin's phenotype to a greater extent in MZ than DZ pairs. We also show that the analysis of sum scores typically biases both MZ and DZ correlations compared to the true latent trait correlation. These two sources of bias are quantified for a range of values and are shown to be especially acute for sum scores based on binary items. Solutions to these problems include formal tests for measurement invariance across zygosity prior to analysis of the sum or scale scores, and multivariate genetic analysis at the individual item or symptom level.
Incorporation of sex-limitation (genotype-sex interaction) effects into a model of quantitative trait loci (QTL) analysis has been shown to increase the power to detect linkage when analyzing traits in which sex limitation is present (Towne et al., 1997). The present note provides a parameterization of the nonscalar sex-limitation ACE model incorporating autosomal sex-limited QTL effects for use with the Mx matrix algebra program (Neale et al., 2002). An example script designed for use with extended sib- ships that takes advantage of the versatile treatment of covariates within Mx is included.
Alcohol abuse and dependence are among the most common psychiatric conditions identified in epidemiological surveys of the general population. The aim of this article is to examine the psychometric properties of Diagnostic and Statistical Manual of Mental Disorders, (4th ed.; DSM-IV; American Psychiatric Association, 1994) criteria for alcohol abuse and dependence using latent class analysis (LCA). Six thousand two hundred and sixty-five young Australian twins (median age 30 years) were interviewed by telephone between 1996 and 2000 using a modified version of the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA). DSM-IV symptoms of alcohol abuse and dependence were collected by structured diagnostic interview and analyzed using methods of LCA. LCA revealed a 4-class solution for women that classified individuals according to the severity of their alcohol- related problems: no/few problems (66.5%), heavy drinking (23.9%), moderate dependence (7.6%) and severe dependence (2.0%). Among men the preferred solution included 5 classes corresponding to no/few problems (46.4%), heavy drinking (34.3%), moderate dependence (12.2%), severe dependence (3.0%) and abuse (4.0%). Evidence of a male-specific class of alcohol-related problems corresponding to abuse partially supports the DSM conceptualization of alcohol use disorders but suggests that this conceptualization — and measurement — may need to be refined for women. Identification of a male- specific abuse class also has important implications for interventions and treatment as these individuals experienced significant alcohol-related problems and comprised approximately 21% of all men classified with an alcohol use disorder.
The genetic etiology of mathematical and reading (dis)ability has been studied in a number of distinct samples, but the true nature of the relationship between the two remains unclear. Data from the Netherlands Twin Register was used to determine the etiology of the relationship between mathematical and reading (dis)ability in adolescent twins. Ratings of mathematical and reading problems were obtained from parents of over 1500 twin pairs. Results of bivariate structural equation modeling showed a genetic correlation around .60, which explained over 90% of the phenotypic correlation between mathematical and reading ability. The genetic model was the same for males and females.
Although it has been suggested that genetic influences on reading difficulties may differ in boys and girls, results obtained from previous analyses of data from same-sex twin pairs have failed to provide evidence for a differential genetic etiology of reading disability (RD) as a function of gender. However, results of a recent study in which data from both same-sex and opposite-sex twin pairs were analyzed indicated a higher heritability for reading difficulties in boys (Harlaar et al., 2005). Because the current sample of twin pairs tested in the Colorado Learning Disabilities Research Center is substantially larger than that analyzed for our previous report (Wadsworth et al., 2000), this hypothesis was tested more rigorously using data from both same-sex and opposite-sex twin pairs in our current augmented sample. Composite reading scores from 634 twin pairs were subjected to DeFries–Fulker sex-limitation analysis using the model-fitting approach of Purcell and Sham (2003). Analysis of data from the combined sample of male and female twins indicated that genetic influences account for more than half the proband reading deficit (h2g = .58). When this model was extended to test for gender differences in the magnitude of genetic influences on RD, h2g estimates were somewhat higher for females than for males (.63 and .53, respectively), but the difference was nonsignificant (p > .3). A test for qualitative gender differences was also nonsignificant. Thus, these results provide little evidence for a differential genetic etiology of RD in boys and girls.
This study examined the genetic and environmental relationships among 5 academic achievement skills of a standardized test of academic achievement, the Queensland Core Skills Test (QCST; Queensland Studies Authority, 2003a). QCST participants included 182 monozygotic pairs and 208 dizygotic pairs (mean 17 years ± 0.4 standard deviation). IQ data were included in the analysis to correct for ascertainment bias. A genetic general factor explained virtually all genetic variance in the component academic skills scores, and accounted for 32% to 73% of their phenotypic variances. It also explained 56% and 42% of variation in Verbal IQ and Performance IQ respectively, suggesting that this factor is genetic g. Modest specific genetic effects were evident for achievement in mathematical problem solving and written expression. A single common factor adequately explained common environmental effects, which were also modest, and possibly due to assortative mating. The results suggest that general academic ability, derived from genetic influences and to a lesser extent common environmental influences, is the primary source of variation in component skills of the QCST.
The aim of this study was to investigate familial influences and their dependence on sex for panic disorder and/or agoraphobia, social phobia, generalized anxiety disorder and major depression. Data from Australian (N = 2287) and Dutch (N = 1185) twins and siblings who were selected for a linkage study and participated in clinical interviews to obtain lifetime Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) diagnoses were used. In a liability model, tetrachoric correlations were estimated in sibling pairs and sex differences between sibling correlations were tested. For each diagnosis, the sibling correlations could be constrained to be equal across the Australian and Dutch samples. With the exception of panic disorder and/or agoraphobia, all sibling correlations were the same for brother, sister and opposite-sex sibling pairs and were around .20. For panic disorder and/or agoraphobia, the correlation was .23 in brother and sister pairs, but absent in opposite-sex sibling pairs. From these results it can be concluded that upper heritability estimates, based on twice the correlations in the sibling pairs, vary between 36% (major depression) and 50% (social phobia). Furthermore, different genetic risk factors appear to contribute to the vulnerability for panic disorder and/or agoraphobia in men and women. No other sex differences were found.
Genes involved in pathways regulating body weight may operate differently in men and women. To determine whether sex-limited genes influence the obesity-related phenotype body mass index (BMI), we have conducted a general non- scalar sex-limited genome-wide linkage scan using variance components analysis in Mx (Neale, 2002). BMI measurements and genotypic data were available for 2053 Australian female and male adult twins and their siblings from 933 families. Clinical measures of BMI were available for 64.4% of these individuals, while only self-reported measures were available for the remaining participants. The mean age of participants was 39.0 years of age (SD 12.1 years). The use of a sex-limited linkage model identified areas on the genome where quantitative trait loci (QTL) effects differ between the sexes, particularly on chromosome 8 and 20, providing us with evidence that some of the genes responsible for BMI may have different effects in men and women. Our highest linkage peak was observed at 12q24 (–log10p = 3.02), which was near the recommended threshold for suggestive linkage (–log10p = 3.13). Previous studies have found evidence for a quantitative trait locus on 12q24 affecting BMI in a wide range of populations, and candidate genes for non- insulin-dependent diabetes mellitus, a consequence of obesity, have also been mapped to this region. We also identified many peaks near a –log10p of 2 (threshold for replicating an existing finding) in many areas across the genome that are within regions previously identified by other studies, as well as in locations that harbor genes known to influence weight regulation.
The association between high and low levels of emotional reactivity (ER) as a temperamental trait and the dopamine D4 receptor (DRD4) exon III polymorphism in healthy men aged 18 to 27 (M= 21.03, SD = 2.23) was examined. ER, measured by the Formal Characteristics of Behavior–Temperament Inventory (FCB-TI), is defined as a tendency to react intensively to emotion-generating stimuli and is expressed in high emotional sensitivity and in low emotional endurance. Data analysis demonstrated a statistically significant difference in the distribution of genotypic frequencies between the low and high ER groups: χ2 = 4.88; df = 1; p = .027, odds ratio (OR) =2.85, 95% confidence interval (CI) = 1.11–7.32. An insignificant difference in allele frequencies between the two groups was noted: χ2 = 7.47; df = 3; p = .058; OR = 2.9, 95% CI = 1.29–6.53. These findings suggest a role of the DRD4 exon III polymorphism in the modulation of ER as a temperamental trait. Due to the preliminary nature of our findings, replication is necessary.
Birthweight has implications for physical and mental health in later life. Using data from Caucasian twins collected in Australia, the Netherlands and the United States, and from East Asian twins collected in Japan and South Korea, we compared the total phenotypic, genetic and environmental variances of birthweight between Caucasians and East Asians. Model-fitting analyses yielded four major findings. First, for both males and females, the total phenotypic variances of birthweight were about 45% larger in Caucasians than in East Asians. The larger phenotypic variances were mainly attributable to a greater shared environmental variance of birth- weight in Caucasians (ranging from 62% to 67% of variance) than Asians (48% to 53%). Second, the genetic variance of birthweight was equal in Caucasians and East Asians for both males and females, explaining a maximum of 17% of variance. Third, small variations in total phenotypic variances of birthweight within Caucasians and within East Asians were mainly due to differences in nonshared environmental variances. We speculate that maternal effects (both genetic and environmental) explain the large shared environmental variance in birthweight and may account for the differences in phenotypic variance in birthweight between Caucasians and East Asians. Recent molecular findings and specific environmental factors that are subsumed by maternal effects are discussed.
The purpose of this study was to examine the genetic contribution to handedness and footedness in childhood using one of the largest available databases of Japanese twins. The participants were 1131 twin pairs, 1057 males and 1205 females, of 11 or 12 years of age (6th grade of secondary school in the Japanese education system). All data were gathered by questionnaire. The prevalence of left (nonright) handedness was 15% in males and 13% in females. The prevalence of left (nonright) footedness was 13% in males and 11% in females. The similarities between twin pairs, estimated by concordance rates and tetrachoric correlations, suggested a slight genetic effect on male handedness, no genetic effect on female handedness, and no genetic effect on footedness in either sex. Structural equation modeling showed small genetic factors (11%) in male handedness and no genetic factors in female handedness. As to footedness, no genetic factors were observed in either sex. The effects of nonshared environmental factors were large (85%) in males and moderate (44%) in females. Moreover, handedness and footedness tended to be concordant irrespective of sex, with polychoric correlations over r = .70. The results of bivariate genetic analyses were not necessarily satisfactory. For males, no model fit. For females, shared and nonshared environmental factors explained the concordance of handedness and footedness. It was concluded that the genetic effects on handedness and footedness are relatively small, as is their association; moreover, considerably large twin samples are needed to obtain stable and appropriate results.
The aims of this study were to identify factors associated with birthweight, birth length and head circumference for triplets, and analyze these body size parameters at birth, especially head circumference, according to gestational age. The subjects of this study were 370 mothers and their 1109 triplet children (excluding one stillborn infant) who were born between 1978 and 2002. The gestational age proved to be the strongest contributing factor to birthweight, birth length and head circumference of the triplets. Moreover, sex was a significant factor affecting birthweight, birth length and head circumference. Male neonates had a higher birthweight, longer birth length and greater head circumference than female neonates. Birth order in triplets also had a significant effect on birthweight and head circumference. Lower birth- order neonates had a higher birthweight and greater head circumference. An effect of maternal pregravid body mass index (BMI) on both birth- weight and birth length was observed. The birthweights of triplets born to women whose pregravid BMIs were more than 26.0 kg/m2 weighed an average of 150 g more than those of triplets born to women whose pregravid BMIs were less than 19.8 kg/m2, and the birth length of triplets born to women whose pregravid BMIs were more than 26.0 kg/m2 averaged 1.5 cm longer than those of triplets born to women whose pregravid BMIs were less than 19.8 kg/m2. Concerning head circumference, the median head circumference of male neonates was approximately 0.5 cm longer than female neonates. Compared to singleton neonates, the median head circumference of triplets was almost the same.