Unaffected Twin Research Articles

Genetic and environmental effects on offspring alcoholism: new insights using an offspring-of-twins design.

Although there is now considerable evidence that genetic effects play a critical role in the development of alcohol dependence (AD), theoretical and methodological limitations of this literature require caution in describing the etiology and development of this disorder. To disentangle genetic and environmental effects on AD by means of the infrequently used, yet potentially powerful, offspring-of-twins design. Offspring of twins. Male monozygotic and dizygotic twins concordant or discordant for AD and control pairs from the Vietnam Era Twin Registry were assessed, as were the offspring of these twins and the mothers of these offspring. Structured psychiatric interviews. Participants' psychiatric, alcohol abuse (AA), and AD histories (DSM-IV). Offspring of monozygotic and dizygotic twins with a history of AD were significantly more likely to exhibit AA or AD than were offspring of nonalcoholic fathers. Offspring of an alcohol-abusing monozygotic twin whose co-twin was AD were also more likely to exhibit AD than were offspring of nonalcoholic twins. In contrast, offspring of an unaffected (ie, no history of abuse or dependence) monozygotic twin whose co-twin was AD were no more likely to exhibit AA or AD than were offspring of nonalcoholic twins. These findings support the hypothesis that family environmental effects do make a difference in accounting for offspring outcomes, in particular, that a low-risk environment (ie, the absence of parental alcoholism) can moderate the impact of high genetic risk regarding offspring for the development of alcohol-use disorders.

A 90-year-old monozygotic female twin pair discordant for Alzheimer’s disease

The present study describes PET, MRI, and neuropsychological findings in 90-year-old monozygotic female twins, who have remained discordant for probable Alzheimer’s disease (AD) for at least 7 years. These findings were compared with those of healthy persons composing the reference group (seven women, three men; the mean±S.D. age: 73.3±3.3 years). Twins’ life histories were remarkably similar, except for continuous NSAID use of the unaffected twin for decades. The regional cerebral glucose metabolic rates (rCMRgluc) and all but two CERAD test scores of the affected twin were more than 2 S.D. below the mean values of the reference group. These values were normal in the unaffected twin. The affected twin had moderate hippocampal and temporoparietal atrophy, whereas the hippocampi were intact, and cortical atrophy was mild in the unaffected twin. These findings indicate that the twins were discordant for AD, even though they had reached the age in which the prevalence of AD is high among women. Our results further address the influence of environmental factors on the onset of AD, especially the possible protective effect of anti-inflammatory medication.

EEG synchronization and spatial working memory in schizophrenia patients, their unaffected twins, and controls

EEG synchronization and spatial working memory in schizophrenia patients, their unaffected twins, and controls

The Influence of Genetics and Environmental Factors in the Pathogenesis of Acne: A Twin Study of Acne in Women

Acne is common and often leads to significant psychologic and physical morbidity. From clinical experience, acne appears to run in families; however, very few studies have investigated the genetic basis of this very common skin disease. A large twin study based on 458 pairs of monozygotic and 1099 pairs of dizygotic twins, all women with a mean age of 46 y was performed to investigate the relative contribution of genetic and environmental factors on the liability to acne. In addition, potential risk factors were assessed in twins with and without acne in a nested cross-sectional design. Fourteen percent of the twins reported a history of acne. Genetic modeling using acne scores showed that 81% (95% confidence interval 73-87%) of the variance of the disease was attributable to additive genetic effects. The remaining 19% was attributed to unique (i.e., unshared) environmental factors. Of the potential risk factors tested in 400 acne twins and 2414 unaffected twins, only apolipoprotein A1 serum levels were significantly lower in acne twins even after adjusting for age and weight. Family history of acne was also significantly associated with an increased risk. No significant differences were found between acne twins and nonacne twins for weight, body mass index, height, birth weight, hair thinning, reproductive factors as well as cholesterol, triglycerides, high-density lipoprotein, and glucose levels. The lower serum levels of apolipoprotein A1 in acne twins were also confirmed when analyzing acne discordant twin pairs. The evidence of a major genetic influence on acne should stimulate the search for potential genes that may lead to new therapeutic approaches.

A Case Report of Cutis Laxa in One of Identical Twins

A 29-year-old man with cutis laxa presented requesting surgery to improve his appearance. The patient had an unaffected identical twin brother which allowed us to compare how he had changed over the years in relation to his sibling and this also provided us with a gold standard for any surgery performed. The patient underwent staged surgery including upper lid blepharoplasties and two facelifts.

Risk factors for breast cancer at young ages in twins: an international population-based study.

Breast cancer etiology in women may relate to exposures early in life as well as in adulthood, but it has been difficult to gain information on childhood variables, and evidence on their effects is very limited. Comparison of risk factor levels between affected probands and unaffected twins in twin pairs can provide a unique method to investigate risk factors that act in early life. We conducted four population-based case-control studies of breast cancer risk in twins in Denmark, England and Wales, Finland, and Sweden and pooled the data from these studies. The case patients were 400 women with incident breast cancer before the age of 50 years, and the control subjects were their twin sisters who had not had breast cancer by that time. Data on risk factors (e.g., demographic and anthropomorphic variables, reproductive history, and family history) were collected by interview and by a mailed questionnaire and were analyzed by calculating matched odds ratios [ORs]. All statistical tests were two-sided. The risk of breast cancer was increased for women who were less obese (OR = 1.44, 95% confidence interval [CI] = 1.08 to 1.91) or taller (OR = 1.27, 95% CI = 0.95 to 1.70) than their co-twin at age 10 years, for women who developed breasts earlier than their co-twin (OR = 1.53, 95% CI = 1.14 to 2.06), and for women who had a smaller waist-to-hip ratio at age 20 years than their co-twin (OR = 1.79, 95% CI = 1.00 to 3.21). Analysis according to family history of breast cancer showed that the associations of childhood height and weight with risk of breast cancer were only apparent in women without a family history of breast cancer. Childhood growth before puberty may affect the risk of premenopausal breast cancer, at least in women without a family history of breast cancer. The distribution of body fat in young adulthood may also be related to breast cancer risk.

Two cases of the caudal duplication anomaly including a discordant monozygotic twin

We present two unrelated patients with various duplications in the caudal region. One patient presented with a duplication of the distal spine from L4, left double ureter, duplication of the vagina and cervix, and duplication of the distal colon. The second patient was diagnosed with a duplication of the colon, bladder, vagina and uterus. The first patient had an unaffected monozygotic twin sister. Dominguez et al. [1993: Am J Dis Child 147:1048-1052] presented six similar cases, and introduced the name "caudal duplication syndrome." The pathogenesis of the caudal duplication anomaly is unclear. The possibility of a polytopic primary developmental field defect or a disruptive sequence are discussed. On the other hand, somatic or germline mutations in certain developmental genes could be involved, as illustrated by the mouse mutations disorganisation and fused. DNA-analysis of the AXIN1 gene, the human homologue of the gene responsible for fused, performed in our first patient, did not show any apparent pathogenic mutation.

Further evidence for a strong genetic influence on the development of autoimmune thyroid disease: the California twin study.

To determine the heritable component of Graves' disease (GD) more precisely, a disease survey questionnaire completed by 13,726 California-born twin pairs over the age of 37 years was used as the foundation of this study. On the basis of this survey, each member of pairs reporting a past diagnosis of GD was then sought for an extensive telephone interview to seek diagnostic confirmation. Successful diagnostic evaluation occurred in 108 cases, of which 99 affected twin pairs form the basis of this report. The results indicate that the estimated pairwise concordance for is 17% in monozygotic (MZ) twins, and 1.9% in dizygotic (DZ) twins, which are in close agreement with a recent report from a Danish twin population. Moreover, the reported 3.9% occurrence of GD found in the first-degree relatives of affected twin pairs supports these findings. In contrast, only 0.45% of all twins, 0.27% of the spouses of twins, and approximately 0.16% of the first-degree relatives of unaffected twins were reported to have GD. Additionally, among the unaffected MZ twins of patients with GD, 17% reported having chronic thyroiditis and 10% other nonthyroid autoimmune conditions such as lupus erythematosus, pernicious anemia, or idiopathic thrombocytopenic purpura. Thus, a genetic predisposition appears to be shared for both thyroid and some nonthyroid autoimmune diseases. While it seems that GD is a strongly and nonspecifically heritable condition, the relatively low level of twin concordance indicates that this disease likely requires a nonheritable etiologic determinant(s) as well.

Altered Colonic Glycoprotein Expression in Unaffected Monozygotic Twins of Inflammatory Bowel Disease Patients

Altered Colonic Glycoprotein Expression in Unaffected Monozygotic Twins of Inflammatory Bowel Disease Patients

Comparison of the Perinatal Morbidity and Mortality of the Presenting Twin and Its Co-Twin

To compare the perinatal outcome of the presenting twin to its co-twin. All live nonanomalous twin gestations delivered at >25 weeks' gestation between 1984 and 1994 (N=461) were identified. Twin A was compared to twin B regarding the following variables: presentation, Apgar score (AS) <4 at 1 minute, AS <7 at 5 minutes, birth weight, gender, traumatic delivery, meconium-stained amniotic fluid, cord prolapse, need for mechanical ventilation, intraventricular hemorrhage, respiratory distress syndrome, sepsis, seizures, perinatal mortality, and length of nursery stay. Except for differences in presentation, the perinatal outcome was similar in both twins regarding variables studied. This continued to hold true after subdividing according to mode of delivery, when infants with birth weight < or = 1500 g were considered separately, and when vaginally delivered cephalic twin A was compared to the noncephalic co-twin. However, differences in some outcome variables became evident when pregnancies with only one affected member were analyzed separately. When all twin pairs are considered, the outcome of the second-born twin is similar to that of the first-born regardless of the mode of delivery, presentation, or birth weight < or = 1500 g. If only those twin pairs with one affected and one unaffected twin are considered, it becomes apparent that the presenting twin is at increased risk for infection-related morbidities whereas the co-twin is at risk for other complications.

Discordant KCNQ1OT1 imprinting in sets of monozygotic twins discordant for Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) presents with visceromegaly, macroglossia, tumor predisposition and other congenital abnormalities, and is usually associated with abnormalities of chromosome 11p15. A number of identical twin pairs, mostly female, have been reported to be discordant for BWS. We show here that the incidence of female monozygotic twins among patients with BWS is dramatically increased over that of the general population. A cluster of imprinted genes within 11p15 is thought to be coordinately regulated via the imprinted expression of KCNQ1OT1, which encodes an untranslated RNA. In skin fibroblasts from five monozygotic twin pairs discordant for BWS, each affected twin had an imprinting defect at KCNQ1OT1 on 11p15, whereas the unaffected twin did not. Five additional monozygotic twin pairs, for whom only blood was available, also displayed an imprinting defect at KCNQ1OT1. It is possible that discordance for BWS in MZ twins is due to unequal splitting of the inner cell mass during twinning, thereby causing differential maintenance of imprinting at KCNQ1OT1. Alternatively, we propose that KCNQ1OT1 is especially vulnerable to a loss of imprinting event, caused by a lack of maintenance DNA methylation at a critical stage of preimplantation development, and that this loss of imprinting predisposes to twinning as well as to discordance for BWS. These data underscore the importance of continued surveillance of children born following assisted reproductive technologies that impact the preimplantation embryo.

Kabuki syndrome: report of six Thai children and further phenotypic and genetic delineation.

We describe six Thai children with the Kabuki syndrome. Monozygotic twin boys discordant for the syndrome were encountered in a family. The affected twin had all five cardinal features of the syndrome, whereas the unaffected twin had none of them. The presence of monozygotic twins discordant for the syndrome argues against a single gene origin of the disorder, but by no means excludes it. In another family, a mother had a facial appearance similar to her affected son. Lower lip pits with or without symmetrical lower lip nodules were present in three of the six children, and pilonidal sinus was seen in five children. These clinical manifestations were much more common than previously described. Other inconsistent findings included early eruption of the lower central incisors, a skin defect of the head, and transient hyperthyrotropinemia in infancy.

Motor immaturity and specific speech and language impairment: evidence for a common genetic basis.

Previous studies have found an association between motor immaturity and specific language impairment in children. Data from two twin studies were used to address the question of whether these linked deficits have a common etiology. Study 1 involved 57 MZ and 22 DZ pairs where one or both twins had specific speech/language impairment. A control group of 173 single-born children was also tested. Motor skill was assessed using a tapping task, which was carried out with left and right hands. Tapping scores were converted to scaled scores adjusted for age and sex. Unaffected twins and single-born controls did not differ in motor skill, but twins with speech and/or language impairments obtained significantly poorer tapping scores than controls. Bivariate DeFries-Fulker analysis pointed to shared genetic influence on tapping speed and a measure of speech production accuracy. In study 2, 37 twin pairs from study 1 were retested 2-3 years later and combined with 100 twin pairs from a general population sample. A timed peg-moving task was used to assess motor skill. Children with combined speech and language impairments obtained poorer peg-moving scores than unaffected children. Bivariate DeFries-Fulker analysis found significant shared genetic variance for impairments on peg-moving and on a test of nonword repetition. It is concluded that genes that put the child at risk for communicative problems also affect motor development, with the association being most evident when speech production is affected.

Reduced Smell Activity May Point To Schizophrenia Predisposition

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessReduced Smell Activity May Point To Schizophrenia PredispositionJoan Arehart-TreichelJoan Arehart-TreichelSearch for more papers by this authorPublished Online:17 Aug 2001https://doi.org/10.1176/pn.36.16.0018aSeveral years ago, Lili Kopala, M.D., a psychiatrist with Dalhousie University in Halifax, Nova Scotia, Canada, and her colleagues examined smell acuity in identical twins discordant for schizophrenia. The twins with schizophrenia had considerable olfaction impairment compared with healthy controls, but the twins without schizophrenia had some impairment as well. The unaffected twins’ performance fell midway between that of the affected twins and that of the healthy controls.Fifty-eight percent of patients with schizophrenia, 34 percent of nonschizophrenia subjects from families with schizophrenia, and 9 percent of healthy controls had senses of smell in the impaired range. “Impaired” was defined as a score on the University of Pennsylvania Smell Identification Test of less than 34 of 40 for men and less than 35 of 40 for women. (Source: Lili Kopala, M.D., et al., Dalhousie University, Halifax, Nova Scotia)This finding made Kopala and her coworkers wonder whether smell impairment might indicate a genetic susceptibility to schizophrenia in persons coming from families with a genetic predisposition to the disease. So they decided to test their hypothesis in another study.The results, reported in the August American Journal of Psychiatry, confirm their hypothesis, Kopala and her colleagues believe.Kopala and her coworkers gave a smell identification test to three groups of subjects younger than age 65. The first group consisted of 19 individuals with schizophrenia who came from families that had had various members with schizophrenia throughout the generations. In other words, it was clear that a strong genetic predisposition to schizophrenia was present in these families.The second group consisted of 27 persons who also came from these families but who did not have schizophrenia. These individuals presumably had some genetic predisposition to schizophrenia as well, but had not developed schizophrenia.A third group consisted of 43 healthy volunteers who were matched for age and gender to each schizophrenia and nonschizophrenia subject; an adequate match for three subjects could not be found.The researchers then compared olfactory test results among the three groups. As they expected, subjects with schizophrenia performed worst on the test, healthy controls best, and subjects without schizophrenia but presumably with some genetic vulnerability to the disease in-between. Specifically, 58 percent of schizophrenia patients, 34 percent of nonschizophrenia subjects, and nine percent of healthy controls performed in the impaired range (see chart).Thus, “impaired olfactory deficits may aggregate in families with schizophrenia and may be indicative of a genetic predisposition to psychosis,” Kopala and her colleagues conclude.The report, “Impaired Olfactory Identification in Relatives of Patients with Familial Schizophrenia,” is posted on the journal’s Web site at ajp.psychiatryonline.org under the August issue.▪ AM J PSYCHIATRY20011581286 ISSUES NewArchived

Preimplantation testing for phenylketonuria

Objective: To use preimplantation genetic diagnosis to achieve a phenylketonuria-free pregnancy in a couple at 50% risk for producing an affected child.Design: DNA analysis of the first and second polar bodies (PB1 and PB2) obtained from oocytes of a heterozygous mother in IVF-ET, with the goal of identifying and transferring back to the patient the embryos resulting from mutation-free oocytes.Setting: IVF program of Reproductive Genetics Institute, Chicago, Illinois.Patient(s): A mother carrying the R408W mutation and a father with compound heterozygosity for R408 and Y414C mutations in phenylalanine hydroxylase (PAH) gene.Intervention(s): Removal and testing for maternal mutation in PB1 and PB2 from each oocyte after standard IVF.Main Outcome Measure(s): DNA analysis of PB1 and PB2 indicating whether corresponding oocytes were mutation-free, for the purposes of transferring only unaffected embryos resulting from these oocytes.Result(s): Of 11 zygotes with both PB1 and PB2, 6 were predicted to be free of phenylketonuria. Of these, 4 were transferred, resulting in an unaffected twin pregnancy and birth of two healthy children.Conclusion(s): Preimplantation genetic diagnosis of phenylketonuria resulted in the birth of phenylketonuria-free children. Preimplantation genetic diagnosis by PB analysis in couples with a compound heterozygous male partner is clinically useful.

A comparison of family functioning, temperament, and childhood conditions in monozygotic twin pairs discordant for lifetime bulimia nervosa.

The authors investigated differences between twins in nine pairs of female monozygotic twins in the Australian Twin Registry who were discordant for lifetime bulimia nervosa. The twins affected and unaffected by lifetime bulimia nervosa were compared on self-report measures, including a measure of parental bonding, four measures of temperament, and six early-childhood medical conditions. No twins had current bulimia nervosa, and there was no difference in weight or eating status between the affected and unaffected twins. The affected twins reported significantly lower self-esteem and less warmth but more overprotection by their mothers during childhood. Although limited by the small number of discordant twin pairs and the inability to detect causal relationships, these results suggest that environmental influences that promote low self-esteem may also increase the risk for bulimia nervosa. These temperamental differences may explain the discrepancies in parenting or perceived parenting.

A volumetric magnetic resonance imaging study of monozygotic twins discordant for bipolar disorder

Six monozygotic (MZ) twin pairs discordant for bipolar disorder were compared with normal MZ twins with magnetic resonance imaging (MRI) on volumes of basal ganglia (BG), amygdala-hippocampus (AH), and cerebral hemisphere. Caudate nuclei were larger in both affected and unaffected bipolar twins than in normal MZ twins. The right hippocampus was smaller in the sick vs. well bipolar twins. The hippocampus was also less asymmetric in the affected bipolar twins than in the well cotwins and the normal MZ twins. These anatomical structures continue to be of interest in bipolar disorder research.

Bone marrow transplantation in multiple sclerosis.

There is strong circumstantial evidence that multiple sclerosis (MS) is an autoimmune disease. Nonspecific immunosuppressive therapy has not been successful in altering the natural course of the illness. Bone marrow transplantation has heretofore been a radical therapy used in patients with life-threatening malignancies but has potential as a treatment for human autoimmunity. In MS there have been no controlled studies. We report here four patients with MS undergoing bone marrow transplantation with 6-48 months of follow-up. In three this was carried out for co-existing malignancy and in one as an experimental treatment for MS using the patient's unaffected identical twin as a donor. The limited outcome that can be evaluated in these patients supports further experimentation into this treatment modality in MS patients with poor prognostic indications.

The Heritability of Polymorphic Light Eruption

Polymorphic light eruption is classified as an acquired idiopathic photodermatosis, yet it appears to cluster in families, suggesting a possible genetic component. In this study, we assess the heritability of polymorphic light eruption using the classical twin model. Polymorphic light eruption was investigated by a nurse-administered questionnaire in a sample of 420 pairs of adult female twins from St Thomas' Hospital UK Adult Twin Registry, including 119 monozygotic and 301 dizygotic pairs. Probandwise concordance for the presence and absence of disease was calculated and the heritability of polymorphic light eruption assessed by a quantitative genetic model fitting approach using Mx software. The prevalence of polymorphic light eruption was 21% and 18% in monozygotic and dizygotic twins, respectively. A family history of polymorphic light eruption in first-degree relatives (not including the cotwin) was present in 12% of affected twin pairs (where at least one twin had polymorphic light eruption) compared with 4% of unaffected twin pairs, providing evidence of familial clustering (p < 0.0001). The probandwise concordance for polymorphic light eruption was higher in monozygotic (0.72) than in dizygotic twin pairs (0.30), indicating a strong genetic effect. Quantitative genetic modeling found that a model comprising additive genetic (A) and unique environmental (E) factors provided the most parsimonious fit, although a dominant gene effect could also explain our data. In the AE model, 84% (95% confidence interval 65-94%) of the variance in susceptibility to polymorphic light eruption is attributed to additive genetic factors with the remaining 16% (95% confidence interval 6-35%) to unique environmental effects. These data establish a clear genetic influence in the expression of polymorphic light eruption and provide a basis for examining candidate genes that may be pathogenic in this common condition.

Application of life table analysis to the onset of dementia in a genetically informative design

The primary objective of this study was to estimate the survival function for time to onset of dementia in initially unaffected twins from when their partner (index proband) was diagnosed with dementia of the Alzheimer's type. Survival functions generated by life table analyses were compared by zygosity and gender. Sixty-one twin pairs where at least one member had been diagnosed with dementia of Alzheimer's type were included in the analyses. Additionally, both members of the twin pair had to be alive at the time the index proband was diagnosed with dementia. The probability of remaining cognitively intact within the first three years after the proband was diagnosed was high (0.93, 95% CI 0.89, 1.0), but after 15 years the probability of remaining intact was low (0.34, 95% CI 0.16, 0.52). Age of onset of the index proband was a significant covariate in the survival functions. There were significant differences in the survival functions for monozygotic (MZ) and dizygotic (DZ) co-twins (chi2 = 3.86, 1, P < 0.05), evidencing a genetic component for age of onset for dementia, but there were no significant differences between men and women.