Twin-family studies of perceptual speed ability. II. Parameter estimation

Offspring of monozygotic (MZ) twins form half-sibships that permit a direct test of maternal effects and differentiate several sources of between-family environmental variance. Combined with conventional twin data, these genetic half-sibships provide a unique data set for estimating sources of variation in quantitative traits. To illustrate, genetic and environmental parameters were estimated for Identical Pictures Test data obtained from children of MZ twin parents and an (approximate) agematched cohort of like-sex twins. Analyses of variance of the data, standardized for age and sex, yield 12 mean squares to which gene-environment models were fit. Maximum-likelihood estimation revealed a complete absence of maternal influences and shared environmental effects; a simple two-parameter model, assuming random mating and attributing variation in test scores to additive genes and within-family environment, adequately accounts for the familial data.This work was supported by the Indiana University Human Genetics Center (GM 21054), a faculty grant-in-aid to RJR, and a postdoctoral fellowship (HL 5863) to JZM; ascertainment and genotyping of twins were supported, in part, by the Specialized Center of Research (SCOR) in Hypertension (HL 14159) and by a grant (HL 20034) from the High Blood Pressure in the Young Program. Portions of this paper were presented by the first author at the Third International Congress on Twin Studies, Jerusalem, 1980.     

X-chromosome inactivation patterns in monozygotic twins and sib pairs discordant for nonsyndromic cleft lip and/or palate

Nonsyndromic clefts of the lip and/or palate are common birth defects with a strong genetic component. Based on unequal gender ratios for clefting phenotypes, evidence for linkage to the X chromosome and the occurrence of several X-linked clefting syndromes, we investigated the role of skewed X chromosome inactivation (XCI) in orofacial clefts. Our samples consisted of female monozygotic (MZ) twins (n = 8) and sister pairs (n = 152) discordant for nonsyndromic clefting. We measured the XCI pattern in peripheral blood lymphocyte DNA using a methylation based androgen receptor gene assay. Skewing of XCI was defined as the deviation in inactivation pattern from a 50:50 ratio. Our analysis revealed no significant difference in the degree of skewing between twin pairs (P = 0.3). However, borderline significant differences were observed in the sister pairs (P = 0.02), with the cleft lip with cleft palate group showing the most significant result (P = 0.01). We did not find evidence for involvement of skewed XCI in the discordance for clefting in our sample of female MZ twins. However, results from the paired sister study suggest the potential contribution of skewed XCI to orofacial clefting, particularly cleft lip and palate.     

Testing for Evidence of an X-Linked Genetic Basis for a Greater Proportion of Males with High Cognitive Ability

X-linked genetic differences between male and females have been posited to cause greater variance in cognitive ability in males. Males with only one X chromosome tend to express the genes on the X chromosome more fully than females, who express an “average” of their two X chromosomes due to X-inactivation. Greater variability in expression of genes on the X chromosome could account for greater variability in male cognitive ability. This would affect both the high and low ends of the cognitive ability distribution, but the possibility of high-end impact has drawn the most attention and controversy. The objective of this paper was to outline a method to test for empirical evidence that greater X-chromosomal variation in males is associated with greater variation in cognitive ability in males at the high end of the distribution. The method utilizes exogenous variation in the maternal X chromosome of twins to test the effect of sex on within-pair variation. We applied this method to g composite test scores at age 10 using data from the Twins Early Development Study. Twin-pair zygosity was used as an instrument reflecting whether twins had different maternal X chromosomes. We estimated differences in the association between variation in the maternal X chromosome in males and females and within-pair variation in test scores using a difference in differences specification of a linear regression model. We found no evidence supporting the proposition that the “averaging” effect of X-inactivation in females resulted in greater variation in male cognitive ability. There was evidence of differential selection for cognitive ability in the sample, however, indicating that the value of our study was primarily to introduce a novel method of addressing the question.     

A premutation that generates a defect at crossing over explains the inheritance of fragile X mental retardation

The view that the Martin-Bell syndrome (X-linked mental retardation with fragile site at Xq27/8) is inherited in a regular X-linked fashion is becoming untenable with the increasing number of reports of transmission through phenotypically normal males. Analysis of the published pedigrees containing such males shows that their heterozygous daughters are never mentally retarded, and have either no fragile site or very few indeed. By contrast, in the next generation, a third of the female heterozygotes are mentally subnormal with an average of 29% fragile sites. These data suggest a premutation that generates the definitive mutation only when transmitted by a female. We propose an inherited sub-microscopic chromosome rearrangement involving the Xq27/8 region that causes no ill effect per se, but generates a significant genetic imbalance when involved in a recombination event with the other X chromosome. This hypothesis explains many of the puzzling genetic aspects of the Martin-Bell syndrome, but it also complicates the interpretation of linkage analysis with genetic markers.     

Genome-wide Scan of IQ Finds Significant Linkage to a Quantitative Trait Locus on 2q

A genome-wide linkage scan of 795 microsatellite markers (761 autosomal, 34 X chromosome) was performed on Multidimensional Aptitude Battery subtests and verbal, performance and full scale scores, the WAIS-R Digit Symbol subtest, and two word-recognition tests (Schonell Graded Word Reading Test, Cambridge Contextual Reading Test) highly predictive of IQ. The sample included 361 families comprising 2–5 siblings who ranged in age from 15.7 to 22.2 years; genotype, but not phenotype, data were available for 81% of parents. A variance components analysis which controlled for age and sex effects showed significant linkage for the Cambridge reading test and performance IQ to the same region on chromosome 2, with respective LOD scores of 4.15 and 3.68. Suggestive linkage (LOD score>2.2) for various measures was further supported on chromosomes 6, 7, 11, 14, 21 and 22. Where location of linkage peaks converged for IQ subtests within the same scale, the overall scale score provided increased evidence for linkage to that region over any individual subtest. Association studies of candidate genes, particularly those involved in neural transmission and development, will be directed to genes located under the linkage peaks identified in this study.     

Genetic and Environmental Causes of Variation in Trait Resilience in Young People

The aim of this multi-informant twin study was to determine the relative role of genetic and environmental factors in explaining variation in trait resilience in adolescents. Participants were consenting families (N = 2,638 twins in 1,394 families), from seven national cohorts (age 12–18 years, both sexes) of monozygotic and dizygotic twins reared together. Questionnaire data on the adolescents’ Ego-resilience (ER89) was collected from mothers, fathers and twins, and analysed by means of multivariate genetic modelling. Variance in trait resilience was best represented in an ADE common pathways model with sex limitation. Variance in the latent psychometric resilience factor was largely explained by additive genetic factors (77% in boys, 70% in girls), with the remaining variance (23 and 30%) attributable to non-shared environmental factors. Additive genetic sources explained more than 50% of the informant specific variation in mothers and fathers scores. In twins, additive and non-additive genetic factors together explained 40% and non-shared environmental factor the remaining 60% of variation. In the mothers’ scores, the additive genetic effect was larger for boys than for girls. The non-additive genetic factor found in the twins’ self ratings was larger in boys than in girls. The remaining sex differences in the specific factors were small. Trait resilience is largely genetically determined. Estimates based on several informants rather than single informants approaches are recommended.     

Heritability of respiratory sinus arrhythmia: Dependency on task and respiration rate

In this study, we investigated the genetic and environmental origin of individual differences in respiratory sinus arrhythmia (RSA) during rest and during four stress tasks. We used a multivariate model including age, RSA, and respiration rate. Participants were 208 male and female pairs of middle-aged twins. A model without sex differences, specifying additive genetic and unique environmental factors, showed the best fit across all conditions. Heritability of RSA ranged from 28% to 43%. Correction for respiration rate yielded RSA heritabilities of similar size. The covariance between respiration rate and RSA was best explained by a combination of correlated unique environmental and correlated additive genetic factors. Combined with data from an earlier project. RSA from 317 adolescent and 712 middle-aged individuals of both sexes was available. This large data set showed that (a) sex differences in mean RSA are absent and (b) RSA decreases considerably from adolescence (111.5 ms) to middle age (60.0 ms).     

A Model Incorporating Potential Skewed X‐Inactivation in MZ Girls Suggests that X‐Linked QTLs Exist for Several Social Behaviours Including Autism Spectrum Disorder

Sex differences in the frequency and patterns of behaviours are frequently observed and largely unexplained. We have investigated the possible role of X‐linked genes in the aetiology of social behaviour problems, including those involved in autistic spectrum disorders. A novel approach has been implemented. This is based on predictions following from stochastic patterns of X‐inactivation of lower concordance of monozygous female (MZF) twins than MZM twins for behaviours underpinned by X‐linked QTLs and the converse that DZF twins are expected to correlate more strongly for X‐linked traits than DZM twins because unlike males, females always have at least one X chromosome in common. These expectations were tested in an ongoing longitudinal cohort study in which all twins born in England and Wales between 1994 and 1996 were invited to take part. 1000 each of MZF, MZM, DZF and DZM pairs from TEDS were tested at 7 and 8 years of age. The results suggest the persistent influence of X‐linked genes on cognition and social behaviour problems, including those involved in autistic spectrum disorders, from early to middle childhood. This emphasises the potential importance of X‐linked genes in the developmental trajectories of behaviour and mental health and the need to stratify genetic analysis of behaviours by gender.     

Sex differences in repetitive stereotyped behaviors in autism: implications for genetic liability

The implications of the well known sex differences in the prevalence of autism spectrum disorder (ASD) are not well understood. The aim of this paper was to investigate whether these differences might be associated with differences in genetic liability. Individuals with ASD (970 families, 2,028 individuals) were recruited as part of the Autism Genome Project (AGP). The families were differentiated into families containing a female (either female-female or male-female) and those with only males. If the sex with the lower prevalence is associated with a greater genetic liability necessary to cross sex-specific thresholds, the males from female containing families should be more severely affected than males from male only families. Affected subjects from the different types of families with ASD were sampled and compared on the social reciprocity and repetitive behavior scores from the Autism Diagnostic Interview-Revised (ADI-R). In general, females had lower repetitive behavior scores than males. More importantly, males from female containing families had higher repetitive behavior scores than males from male-male families. No such differences were apparent on the social reciprocity scores. These results support the hypothesis of a multiple threshold model of genetic liability of ASD with females having a higher liability for affectation status, at least on the repetitive behavior dimension of the disorder. These data also support the dissociation of the different phenotypic dimensions of ASD in terms of its genetic architecture. The implications of these results for linkage and association studies are discussed.     

In pursuit of the “spatial gene”: A family study

Members of 192 families in the Tel Aviv area were given a battery of eight cognitive tests focusing on spatial measures but sampling verbal, numerical, and perceptual speed domains as well. The patterns of parent-child and sibling correlations gave very weak evidence, if any, for the operation of the X-linked recessive gene postulated by Stafford and others to affect performance on tasks involving spatial visualization. An analysis of male and female score distributions provided results more favorable to the X-linkage hypothesis, at least for the child generation, although suggesting that X linkage does not explain the whole male-female difference in performance on spatial tasks.This research was supported by funds from NSF Grant GU-1598 to the University of Texas.     

Specific cognitive abilities in 5- to 12-year-old twins

Eleven tests of specific cognitive abilities were administered to 108 pairs of young twins (average age of 7.6 years). Internal consistencies are high for all measures except Raven's Coloured Progressive Matrices and Delayed Picture Memory. Two-month, test-retest reliabilities are also reported. The twin sample is representative in terms of both means and variances when compared to normative data from standardization samples, and twin correlations for height and weight are similar to those obtained in six other twin studies. Because all measures were highly correlated with age (average correlation with age was 0.64), scores were age adjusted. Previous twin studies of specific cognitive abilities in adolescents and adults found genetic variance for nearly all tests. In contrast, our study of young twins yielded significant genetic influence for only 1 of the 11 measures, PIAT Reading Recognition, and suggested the possibility of genetic influence on 2 others (vocabulary and WISC-R mazes). Environmental influences seem to dominate, particularly for nonverbal measures, as children begin their education. In accord with other studies, we found that between-family environmental factors have an important influence on the development of nearly all of the measures of specific cognitive abilities. However, we found that our tests of perceptual speed and memory were substantially influenced by within-family environmental factors independent of error.This work was supported by a grant from the Spencer Foundation.     

Analysis of Xq27-28 linkage in the international consortium for prostate cancer genetics (ICPCG) families

ABSTRACT: BACKGROUND: Genetic variants are likely to contribute to a portion of prostate cancer risk. Full elucidation of the genetic etiology of prostate cancer is difficult because of incomplete penetrance and genetic and phenotypic heterogeneity. Current evidence suggests that genetic linkage to prostate cancer has been found on several chromosomes including the X; however, identification of causative genes has been elusive. METHODS: Parametric and non-parametric linkage analyses were performed using 26 microsatellite markers in each of 11 groups of multiple-case prostate cancer families from the International Consortium for Prostate Cancer Genetics (ICPCG). Meta-analyses of the resultant familyspecific linkage statistics across the entire 1,323 families and in several predefined subsets were then performed. RESULTS: Meta-analyses of linkage statistics resulted in a maximum parametric heterogeneity lod score (HLOD) of 1.28, and an allele-sharing lod score (LOD) of 2.0 in favor of linkage to Xq27- q28 at 138 cM. In subset analyses, families with average age at onset less than 65 years exhibited a maximum HLOD of 1.8 (at 138 cM) versus a maximum regional HLOD of only 0.32 in families with average age at onset of 65 years or older. Surprisingly, the subset of families with only 2-3 affected men and some evidence of male-to-male transmission of prostate cancer gave the strongest evidence of linkage to the region (HLOD = 3.24, 134 cM). For this subset, the HLOD was slightly increased (HLOD = 3.47 at 134 cM) when families used in the original published report of linkage to Xq27-28 were excluded. CONCLUSIONS: Although there was not strong support for linkage to the Xq27-28 region in the complete set of families, the subset of families with earlier age at onset exhibited more evidence of linkage than families with later onset of disease. A subset of families with 2-3 affected individuals and with some evidence of male to male disease transmission showed stronger linkage signals. Our results suggest that the genetic basis for prostate cancer in our families is much more complex than a single susceptibility locus on the X chromosome, and that future explorations of the Xq27-28 region should focus on the subset of families identified here with the strongest evidence of linkage to this region.     

Search for linkage to schizophrenia on the X and Y chromosomes

Markers for X chromosome loci were used in linkage studies of a large group of small families (n = 126) with at least two schizophrenic members in one sibship. Based on the hypothesis that a gene for schizophrenia could be X-Y linked, with homologous loci on both X and Y, our analyses included all families regardless of the pattern of familial inheritance. Lod scores were computed with both standard X-linked and a novel X-Y model, and sibpair analyses were performed for all markers examining the sharing of maternal alleles. Small positive lod scores were obtained for loci pericentromeric, from Xp11.4 to Xq12. Lod scores were also computed separately in families selected for evidence of maternal inheritance and absence of male to male transmission of psychosis. The lod score for linkage to the locus DXS7 reached a maximum of 1.83 at 0.08% recombination, assuming dominant inheritance on the X chromosome in these families (n = 34). Further investigation of the X-Y homologous gene hypothesis focussing on this region is warranted. © 1994 Wiley-Liss, Inc.     

Heritability of Self-reported Phobic Fear

Twin studies on fear and phobia suggest moderate genetic effects. However, results are inconclusive regarding the presence of dominant genetic effects and sex differences. Using an extended twin design, including male and female twins (n = 5,465) and their siblings (n = 1,624), we examined the genetic and environmental influences on blood-injury, social, and agoraphobic fear and investigated their interaction with sex and age. Data of spouses (n = 708) of twins were used to evaluate assortative mating for the three fear dimensions. Results showed that there was no assortative mating for blood-injury, social and agoraphobic fear. Resemblance between biological relatives could be explained by additive and non-additive genetic effects for blood-injury and agoraphobic fear in all participants, and social fear in participants aged 14–25 years. For social fear in participants aged 26–65 only additive genetic effects were detected. Broad-sense heritability estimates ranged from 36 to 51% and were similar for men and women. Edited by John K Hewitt.     

Linkage analysis of 62 X-chromosomal loci excludes the X chromosome in an Icelandic family showing apparent X-linked recessive inheritance of neural tube defects

We report here the findings of a linkage analysis, involving numerous markers from the human X chromosome, in an attempt to localise a putative gene causing apparent X-linked spina bifida and anencephaly (SBA) in a large Icelandic pedigree. Two-point linkage analysis was performed using markers from 62 informative loci in this family. Although small positive lod scores were found at a number of these loci, none reached the significance level for linkage. Haplotypes were extensively analysed and found to exclude linkage to the X chromosome.     

Failure to establish linkage on the X chromosome in 301 families with schizophrenia or schizoaffective disorder

The hypothesis that a gene for susceptibility to psychosis (specifically in the X-Y homologous class) is located on the sex chromosomes has been proposed. Such a gene would account for the excess of sex chromosome anomalous males and females in populations of patients with psychosis, a tendency towards concordance by sex within families, and sex differences associated with psychosis and its underlying brain pathology. In earlier studies we observed small positive LOD scores in Xp11, and in a more recent and larger cohort of 178 sibling pairs, a peak multipoint nonparametric LOD score of 1. 55 at the locus DXS8032 in Xq21. The present study with a new set of markers extended the cohort to 301 ill sibling pairs and their parents. Despite the increase in sample size, the LOD score did not increase. A peak NPL of 1.55 was observed at the locus DXS1068 in proximal Xp, a region remote from the previous report. Separating families into those who were more likely to have X chromosome inheritance (maternal with no male to male transmission) did not yield stronger findings. In spite of the evidence that psychosis is related to a sex-dependent dimension of cerebral asymmetry, it is concluded that no consistent linkage of schizophrenia to the X chromosome can be demonstrated. In the context of the general failure of replication of linkage in psychosis, the possibility that the genetic predisposition to psychosis is contributed to by epigenetic modification rather than variations in the nucleotide sequence has to be considered.     

Childhood Sexual Abuse Moderates Genetic Influences on Age at First Consensual Sexual Intercourse in Women

We examine interactive effects of childhood sexual abuse (CSA) on heritable variation in age at first consensual sexual intercourse in a young cohort of 3,350 female and 2,724 male Australian twins. Consistent with hypotheses, genetic influences explained little if any variation in age at first consensual sexual intercourse for female twins reporting CSA (CSA(+)), with shared environment explaining 73%. For female twins reporting no history of CSA (CSA(-)), 39% of variation in age at first consensual sexual intercourse was explained by genetic effects, with shared environment accounting for 30%. For male twins, significant interactive effects of CSA on genetic and environmental variation in age at first consensual sexual intercourse were not observed. Overall genetic influences explained 51% of variation in age at first consensual sexual intercourse for male twins, with shared environment accounting for 8%. For both female and male twins, results from models that included conduct disorder as a covariate were near identical to results from models without conduct disorder.     

Twin resemblances in cognitive abilities in an Egyptian sample

Thirty-six pairs of monozygotic (MZ) twins, 24 pairs of same-sexed dizygotic (DZ) twins, and 33 pairs of opposite-sexed DZ twins 12 to 19 years of age were tested in Minia, Egypt, on a battery of cognitive abilities tests. For most of the tests and composite scales, DZ resemblances were higher than typically found in Western samples and not significantly different from MZ resemblances. MZ resemblances were generally lower than typically found in Western samples. These results were discussed in terms of the influence of cross-cultural differences in degree of social stratification and assortative mating.This research was conducted while Anwar Abdel-Rahim was fully supported in the United States by grants from the Egyptian Government Ministry of Education and from Minia University. Dr. Abdel-Rahim wishes to thank Steven Vandenberg and his wife for their help and hospitality during his stay at the Institute for Behavioral Genetics in Boulder and to thank Drs. A. Kuse and K. W. Kang for their statistical advice. This paper was written while Craig Nagoshi was supported by NICHD Training Grant HD-07289.     

Carrier detection of the X-linked primary immunodeficiency diseases using X-chromosome inactivation analysis

Carrier detection of three of the X-linked primary immunodeficiency diseases (X-linked agammaglobulinemia, X-linked severe combined immunodeficiency disease, and the Wiskott-Aldrich syndrome) is possible by analyzing patterns of X-chromosome inactivation in those cells affected by the disorder. Normal women have balanced patterns of X-chromosome inactivation; that is, in a given population of cells, approximately half of their active X chromosomes are of paternal origin and half of their active X chromosomes are of maternal origin. In contrast, female carriers of these X-linked immunodeficiency disorders have an unbalanced pattern of X-chromosome inactivation in those cell lineages that are affected by the disorder; that is, all the active X chromosomes in affected cell lineages are the X chromosomes that carry the normal allele. Two techniques are available for X-chromosome inactivation analysis. One technique depends on methylation differences between the active and inactive X chromosome, and the other technique uses somatic cell hybrids that selectively retain the active X chromosome. In either case, carrier detection can be performed in individuals from families in which only one member of the family has been affected, since neither of these methods depends on linkage analysis.