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Univariate and bivariate analyses of cholesterol and triglyceride levels in pedigrees.

A multivariate normal model for pedigree analysis is applied to fasting total serum cholesterol and total serum triglyceride measurements on 771 individuals in 95 pedigrees from Rochester, MN. Univariate and bivariate analyses are carried out to determine to what extent the aggregation and coaggregation in families of these two traits may be attributed to shared genetic and environmental factors. Pedigrees were ascertained through a sample of schoolchildren enriched for those with serum cholesterol levels in the highest and lowest deciles of their age- and sex-specific distributions. Ascertainment is corrected for by conditioning the likelihood on the trait values of the probands. Univariate results confirm the findings of previous studies indicating that familial aggregation of serum cholesterol and triglyceride levels is due both to shared genes and to shared environmental factors. Results of the bivariate analyses suggest that the coaggregation of cholesterol and triglyceride levels in these families is strongly influenced by both shared genes (pleiotropy) and shared environmental factors. These findings are consistent with our understanding of lipid metabolism and of specific environmental factors known to influence both traits.

Adolescent↗

A new syndrome with features of the Smith-Lemli-Opitz and Meckel-Gruber syndromes in a sibship with cerebellar defects.

The Smith-Lemli-Opitz syndrome (SLOS) and the Meckel syndrome (MS) have been regarded as separate autosomal recessive entities. Recently, overlap of these two syndromes has been discussed. A sibship containing a probable new syndrome with features reminiscent of the SLOS and the MS is presented. The literature is reviewed with regard to the frequency of various malformations in these syndromes. Clinical manifestations and cerebellar abnormalities in these sibs are similar to those described in the Joubert syndrome (JS). These three cases may represent a new syndrome with features in common with SLOS, MS, and JS resulting from the same mutant gene, which exhibits considerable pleiotropy.

Abnormalities, Multiple↗

Renal tubular dysgenesis: delayed onset of oligohydramnios.

Two premature sibs had Potter sequence and died of respiratory failure within the first day. Ultrasonography at 26 weeks during the earlier of the two pregnancies showed complete absence of amniotic fluid, and the urinary bladder was not visualized. Ultrasound examinations during the second pregnancy showed adequate amniotic fluid at 16 and 20 weeks, with a subsequent reduction in fluid volume. Two older sibs had also died of respiratory failure shortly after birth. Postmortem histopathologic studies showed all four sibs to have severely deficient renal tubular development. However, the presence of numerous glomeruli indicated prolific nephrogenesis. Most of the tubules in sections of cortex had the lectin-binding and immunohistochemical characteristics of collecting ducts; proximal tubules were not identified by lectin-binding. Electron-microscopic examination showed a general absence of differentiated characteristics in cortical tubular epithelium, except that rare tubules contained rudimentary proximal tubular brush borders. Three of the sibs were boys, one a girl. The three children that were studied had normal chromosomes. Two unaffected sibs are alive and well. Neither parent has any clinical evidence of renal disease. These studies support the interpretation that renal tubular dysgenesis is autosomal recessive with pleiotropy. However, the relatively late appearance of oligohydramnios makes early diagnosis difficult, even when the condition is suspected.

Amniotic Fluid↗

Genomics of human dysmorphogenesis.

A survey of Mendelian Inheritance in Man emphasizes the large Mendelian contribution to human dysmorphogenesis and contrasts single gene conditions with chromosomal disorders. There were 1761 conditions that involved altered morphogenesis (49% of disease entries), including 1040 multiple defect syndromes and 721 inherited single birth defects. Premature death (36-57%), mental retardation (20-59%), and growth retardation (37-59%) are more frequent in autosomal recessive or X-linked syndromes, while predisposition to tumorigenesis was more common in dominant (16%) than recessive (3.4%) syndromes. Comparison of the Mendelian conditions with 100 chromosomal disorders showed a strikingly similar spectrum of malformation, with skeletal, craniofacial, eye, epidermal, and neuromuscular systems being most frequently affected. Chromosomal syndromes average 10.6 systems affected per disorder, in contrast to 3.55 for Mendelian syndromes, and pleiotropy does correlate weakly with aneuploid segment length. Genomic understanding of these relationships is still primitive, with 74 of 1609 (4.6%) autosomal conditions and 43 of 152 (29%) X-linked conditions mapped to specific chromosomal regions. The societal toll of human dysmorphogenesis and the evident progress with X-linked disorders provide a powerful rationale for the Human Genome Project.

Chromosome Aberrations↗

Autosomal recessive oral-facial-digital syndrome with resemblance to OFD types II, III, IV and VI: a new OFD syndrome?

We report on a son and daughter of Ashkenazi-Jewish parents with postaxial polydactyly of the hands and feet associated with syndactyly and brachydactyly, mental retardation, cerebellar hypoplasia, pectus excavatum, mesomelic shortness of the upper and lower limbs, and pretibial dimples. Although this appears to be an example of one of the OFD syndromes and has many similarities to OFD type II, III, IV and VI, it does not fit satisfactorily into any of the types previously described. Thus this may be a new OFD syndrome, although we cannot exclude a possibility that most or all autosomal recessive OFD syndromes are the result of pleiotropy of a single mutation in a homozygous state.

Adolescent↗

Kohlschütter-Tönz syndrome: epilepsy, dementia, and amelogenesis imperfecta.

Kohlschütter-Tönz syndrome is a central nervous system (CNS) degenerative disease with convulsions and mental regression in which the affected children present with yellow teeth due to defective enamel. We present a family in which 2 affected children (a boy and a girl) were born to consanguineous parents. This report confirms the autosomal recessive inheritance of the disorder. The combination of a CNS and an enamel defect may represent pleiotropy or a contiguous gene syndrome.

Abnormalities, Multiple↗

Meckel on developmental pathology.

Before Schleiden and Schwann, Darwin and Mendel there passed briefly a towering giant, Johann Friedrich Meckel the Younger (1781-1833), now glimpsed only fleetingly and obscurely through the mist of time and former controversies, who can nowadays easily and clearly be identified as the father of a "pre-modern" developmental biology. At his beginning this prodigiously gifted physician-scholar had, as one would say nowadays, an unfair advantage, his cradle having been rocked, as it were, by the preparators in his father's and grandfather's huge collection of normal and abnormal anatomical "specimens" in the home in which he was born and raised including his father's own skeleton (with two anatomical anomalies!). Initially reluctant to follow in the steps of his illustrious anatomist/physician grandfather and father, he nevertheless early demonstrated extraordinary gifts in anatomy and zootomy. Napoleon's conquest of his homeland notwithstanding, Meckel spent at least 2 extremely fruitful years in Paris, under the tutelage of Cuvier, but also in close contact with Geoffroy St. Hilaire (Etienne), Lamarck, and von Humboldt. He not only translated Cuvier's Leçons d'anatomie comparée into German but also greatly enriched this pivotal treatise with observations of embryonic and malformed fetuses and animals only of passing interest to his mentor. In his numerous publications, Meckel was the first to relate abnormal to normal development, define anomalies of incomplete differentiation (vestigia), but, most importantly, to relate those malformations known in humans to those that are normal adult developmental states in "lower" animals (atavisms). Thus, Meckel's three-fold parallelism of the scala naturae, normal ontogeny, and the malformations in humans and animals makes him a recapitulationist par excellence, however, without ever venturing into a fully articulated and explicit theory of descent. Today Meckel is remembered solely as the discoverer of the syndrome and cartilage named after him, and as having interpreted, correctly, the developmental nature of the "Meckel" diverticulum. It is virtually unknown that Meckel also first enuntiated the concept and distinction between primary and secondary malformations/anomalies, introduced the notion of heredity into the causal analysis of congenital anomalies, was the father of syndromology (the Meckel syndrome), had a clear understanding of pleiotropy and heterogeneity, and can unequivocally be regarded as the father of developmental pathology. In hindsight, and inspite of much professional success, Meckel emerges as a tragic figure in the history of biology, his life cut short at 52 without an ability to incorporate cell theory and the embryological insights of his younger contemporaries into his intellectual edifice which might have made it possible for him to finally and clearly see "analogy" (now homology), of which he was the greatest expert in his era, as incontrovertible evidence for descent. In that case, Darwin and Haeckel might have even had the courtesy of a tip-of-the-hat in Meckel's direction.

Abnormalities, Multiple↗

Ethical and clinical practice considerations for genetic counselors related to direct-to-consumer marketing of genetic tests.

Several companies utilize direct-to-consumer (DTC) advertising for genetic tests and some, but not all, bypass clinician involvement by offering DTC purchase of the tests. This article examines how DTC marketing strategies may affect genetic counselors, using available cardiovascular disease susceptibility tests as an illustration. The interpretation of these tests is complex and includes consideration of clinical validity and utility, and the further complications of gene-environment interactions and pleiotropy. Although it is unclear to what extent genetic counselors will encounter clients who have been exposed to DTC marketing strategies, these strategies may influence genetic counseling interactions if they produce directed interest in specific tests and unrealistic expectations for the tests' capacity to predict disease. Often, a client's concern about risk for cardiovascular diseases is best addressed by established clinical tests and a family history assessment. Ethical dilemmas may arise for genetic counselors who consider whether to accept clients who request test interpretation or to order DTC-advertised tests that require a clinician's authorization. Genetic counselors' obligations to care for clients extend to interpreting DTC tests, although this obligation may be fulfilled by referral or consultation with specialists. Genetic counselors do not have an obligation to order DTC-advertised tests that have minimal clinical validity and utility at a client's request. This can be a justified restriction on autonomy based on consideration of risks to the client, the costs, and the implications for society.

Cardiovascular Diseases↗

Interpreting the posture and locomotion of Australopithecus afarensis: where do we stand?

Reconstructing the transition to bipedality is key to understanding early hominin evolution. Because it is the best-known early hominin species, Australopithecus afarensis forms a baseline for interpreting locomotion in all early hominins. While most researchers agree that A. afarensis individuals were habitual bipeds, they disagree over the importance of arboreality for them. There are two main reasons for the disagreement. First, there are divergent perspectives on how to interpret primitive characters. Primitive traits may be retained by stabilizing selection, pleiotropy, or other ontogenetic mechanisms. Alternately, they could be in the process of being reduced, or they simply could be selectively neutral. Second, researchers are asking fundamentally different questions about the fossils. Some are interested in reconstructing the history of selection that shaped A. afarensis, while others are interested in reconstructing A. afarensis behavior. By explicitly outlining whether we are interested in reconstructing selective history or behavior, we can develop testable hypotheses to govern our investigations of the fossils. To infer the selective history that shaped a taxon, we must first consider character polarity. Derived traits that enhance a particular function, are found to be associated with that function in extant homologs, and that epigenetically sensitive data indicate were actually being used for that function, can be interpreted as adaptations. The null hypothesis to explain the retention of primitive traits is that of selective neutrality, or nonaptation. Disproving this requires demonstration of active stabilizing or negative selection (disaptation). Stabilizing selection can be inferred when primitive traits compromise a derived function clearly of adaptive value. Prolonged stasis, continued use of the trait for a particular function, or no change in variability in the trait are evidence that can support a hypothesis of adaptation for primitive traits, but still do not falsify the null hypothesis. Disaptation, or negative selection, should result in a trait being reduced or lost. To infer the behaviors of a fossil species, we must first determine its adaptations, use this to make hypotheses about its behavior, and test these hypotheses using epigenetically sensitive traits that are modified by an individual's activity pattern. When the A. afarensis data are evaluated using this framework, it is clear that these hominins had undergone selection for habitual bipedality, but the null hypothesis of nonaptation to explain the retention of primitive, ape-like characters cannot be falsified at present. The apparent stasis in Australopithecus postcranial form is currently the strongest evidence for stabilizing selection maintaining its primitive features. Evidence from features affected by individual behaviors during ontogeny shows that A. afarensis individuals were habitually traveling bipedally, but evidence presented for arboreal behavior so far is not conclusive. By clearly identifying the questions we are asking about early hominin fossils, refining our knowledge about character polarities, and elucidating the factors influencing morphology, we will be able to progress in our understanding of the posture and locomotion of A. afarensis and all early hominins.

Adaptation, Physiological↗

Genetic and environmental correlations between various anthropometric and blood pressure traits among adult Samoans.

Shared polygenic effects (i.e., pleiotropy) are assumed to exist for such obesity-related phenotypes as blood pressure and adiposity. It is possible to identify these shared genetic effects through bivariate genetic analyses. This analysis of 1,342 adult Samoans, across 801 pedigrees, indicates that significant heritable components (P < 0.05) ranging from 29-58% exist for weight, height, systolic blood pressure, diastolic blood pressure, triceps skinfold, subscapular skinfold, body mass index, and sum of skinfolds. In general, the anthropometric measurements share additive genetic effects, as do the anthropometric measures, with blood pressure. Heritabilities for central fat distribution are not significant in this population, which could be due to a lack of power. On the other hand, heritabilities have been found in Hispanics; hence the genes responsible for central fat distribution may not be evenly distributed among populations.

Adult↗

Aging mechanisms in fruit files.

Genetic analysis of Drosophila has provided evidence in support of two proposed evolutionary genetic mechanisms of aging: mutation accumulation and antagonistic pleiotropy. Both mechanisms result from the lack of natural selection acting on old organisms. Analyses of large numbers of files have revealed that mortality rates do not continue to rise with age as previously thought, but plateau at advanced ages. This phenomenon has implications both for models and for definitions of aging, and may be explained by the evolutionary theories. The physiological processes and genes most relevant to aging are being identified using Drosophila lines selected in the laboratory for postponed senescence. Oxidative stress and insufficient metabolic reserves/capacity may be particularly important factors in limiting the fruitfly lifespan. Genes which exhibit aging-related changes in expression are now being identified. Transgenic files are being used to analyze the mechanisms of such aging-related gene expression, and to test the effects of specific genes on aging and aging-related deterioration.

Aging↗

Association of congenital hypertrophy of the retinal pigment epithelium with familial adenomatous polyposis.

Ophthalmological examinations were performed in 49 people (43 patients) from 24 families affected by familial adenomatous polyposis (FAP). No features of congenital hypertrophy of the retinal pigmented epithelium (CHRPE) were noted in six first-degree relatives without colonic polyps. Patients with Gardner's syndrome exhibited CHRPE more frequently than those without exostosis or desmoid tumour (91 per cent versus 45 per cent). In addition the prevalence of CHRPE was slightly higher in the patients with gastric or duodenal polyps (68 per cent compared with 50 per cent) in those who had a normal gastroduodenal examination. There were 11 families in which two or more patients underwent ophthalmological examinations. In five of these 11 families, all 12 patients were negative for CHRPE. In four of the remaining six families, all 11 patients had CHRPE. CHRPE is one of the pleiotropy of FAP and ophthalmological examination is an important screening test for the family of patients with CHRPE associated with FAP.

Adenomatous Polyposis Coli↗

Mouse orthologue of ARX, a gene mutated in several X-linked forms of mental retardation and epilepsy, is a marker of adult neural stem cells and forebrain GABAergic neurons.

Mutations in the human ARX gene show unusually heterogeneous clinical presentations, including syndromic and nonsyndromic mental retardation, myoclonic epilepsy with spasticity, and lissencephaly with abnormal genitalia, that are believed to arise from an impairment of the embryonic mechanisms building the anterior central nervous system structures. Here, we show that the murine ortholog Arx has a highly dynamic expression pattern during both early shaping of the forebrain vesicle and later major events of neural migrations and cell-type specification. Early on, the Arx gene is specifically activated in anterior forebrain anlage. Afterward, Arx expression is confined to the telencephalic vesicles and is enhanced during differentiation of the subpallial structures of the ganglionic eminences, overlapping with Dlx2, Dlx5, and Gad1 transcriptional domains. Tangentially migrating neurons reaching the cortical plate are also Arx-positive at all embryonic stages analyzed. RNA-protein colabeling staining shows that Arx expression is maintained in the mature cortical interneurons, suggesting its involvement in the different functions of the gamma-aminobutyric acid (GABA)ergic neurons settled into the adult cerebral cortex. Finally, Arx expression is detected in the anterior subventricular layer of the adult brain, where neural stem cells have been shown to be located. Of interest, Arx expression is highly up-regulated during in vitro differentiation of pure neural stem cell cultures retrieved from adult brain. All together, these findings suggest Arx as a gene involved in the commitment of proliferating neuroblasts into a GABAergic neuronal fate. In conclusion, our mouse Arx expression data provide important further insights into the puzzling complexity of the human ARX mutation pleiotropy.

Animals↗

Close association between particular I region-determined cell surface antigens and Ir gene-controlled immune responsiveness to synthetic polypeptides in wild rats.

The relationship between major histocompatibility complex (MHC) and genetic control of immune responsiveness to the synthetic polypeptides (T,G)-A--L [poly-(LTyr,LGlu)-poly(DLAla)--poly(LLys)] and (H,G)-A--L [poly(LHis,L-Glu)-poly-(DLAla)--poly(LLys)] has been studied in 26 wild rats. The major histocompatibility complex (MHC) genotype frequencies observed were not different from those expected according to the Hardy-Weinberg formula. More than half of the wild rats carried MHC-linked responder Ir-TGAL and Ir-HGAL genes. High or intermediate responsiveness to (T,G)-A--L and high responsiveness to (H,G)-A--L were always found to be associated with particular I region-determined cell surface antigens. These antigens could be identified serologically and by primary and secondary mixed lymphocyte reactions, and were similar or identical to I region products of (T,G)-A--L high responder or (H,G)-A--L intermediate responder inbred rat strains. The strong association between cell surface antigens and immune responsiveness could be due to linkage disequilibrium or to pleiotropy. Since the same I region-determined cell surface structure could be associated either with high or intermediate anti-(T,G)-A--L antibody titers, the presence of the Ia antigen(s) identified did not seem to guarantee high antibody responsiveness to the test antigen.

Animals↗

Causal effects of sedentary behaviours on the risk of migraine: A univariable and multivariable Mendelian randomization study.

BACKGROUND: Migraine is a common and burdensome neurological disorder. The causal relationship between sedentary behaviours (SBs) and migraine remains instinct. We aimed to evaluate the roles of SBs including watching TV, using computer and driving in the risk of migraine. METHODS: We conducted a univariable and multivariable Mendelian randomization (MR) study based on summary datasets of large genome-wide association studies. The inverse variance weighted method was utilized as the primary analytical tool. Cochran's Q, MR-Egger intercept test, MR pleiotropy residual sum and outlier and leave-one-out were conducted as sensitivity analysis. Additionally, we performed a meta-analysis to combine the causal estimates. RESULTS: In the discovery analysis, we identified causal associations between time spent watching TV and an increased risk of migraine (p&#x2009;=&#x2009;0.015) and migraine without aura (MO) (p&#x2009;=&#x2009;0.002). Such causalities with increasing risk of migraine (p&#x2009;=&#x2009;0.005), and MO (p&#x2009;=&#x2009;0.006) were further verified using summary datasets from another study in the replication analysis. There was no significant causal association found between time spent using computer, driving and migraine or its two subtypes. The meta-analysis and multivariable MR analysis also strongly supported the causal relationships between time spent watching TV and an increased risk of migraine (p&#x2009;=&#x2009;0.0003 and p&#x2009;=&#x2009;0.034), as well as MO (p&#x2009;<&#x2009;0.0001 and p&#x2009;=&#x2009;0.0004), respectively. These findings were robust under all sensitivity analysis. CONCLUSIONS: Our study suggested that time spent watching TV may be causally associated with an increased risk of migraine, particularly MO. Large-scale and well-designed cohort studies may be warranted for further validation. SIGNIFICANCE STATEMENT: This study represents the first attempt to investigate whether a causal relationship exists between SBs and migraine. Utilizing MR analysis helps mitigate reverse causation bias and confounding factors commonly encountered in observational cohorts, thereby enhancing the robustness of derived causal associations. Our MR analysis revealed that time spent watching TV may serve as a potential risk factor for migraine, particularly MO.

Humans↗

Multivariate segregation analysis using the mixed model.

Most major genes involved in the etiology of complex diseases are likely to have pleiotropic effects on a number of intervening quantitative traits. Methods of segregation analysis that incorporate the additional information from such multiple traits will exhibit greater power for detecting the effects of major genes and allow explicit tests of major locus pleiotropy hypotheses. In this study, we present a new method for multivariate segregation analysis that utilizes a multivariate generalization of Hasstedt's [1982] technique for calculating approximate mixed model likelihoods on pedigrees. The method is based on a simplification of the multivariate conditional likelihood via a transformation that simultaneously orthogonalizes the residual additive genetic and environmental covariance matrices. This transformation allows the multivariate conditional likelihood to be factored into the product of independent univariate conditional likelihoods. Resulting computations are relatively fast, making it feasible to analyze multiple traits in extended pedigrees. We demonstrate our method with a bivariate analysis of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein AI (apo AI) serum levels in 585 pedigreed baboons.

Apolipoprotein A-I↗

Multivariate genetic analysis of an oligogenic disease.

Joint multivariate segregation and linkage analysis provides a method for simultaneously analyzing data on affection status, correlated phenotypic traits, environmental risk factors, and other covariates. The power of this approach for mapping disease susceptibility loci of small effect (oligogenes) was evaluated by analyzing the GAW9 Problem 2 data set. The program REGRESS, which assumes a pleiotropy model in which one locus influences both affection status (AF) and a quantitative trait, was used to conduct joint segregation and linkage analysis of bivariate phenotypes, each comprising AF and one quantitative trait (Q2, Q3, Q4). A genome-wide search using markers spaced approximately 10 cM apart was conducted and regions on chromosomes 1, 2, and 5 were identified as demonstrating linkage with three respective bivariate phenotypes at the following markers: AF/Q2-D1G2; AF/Q3-D2G10; and AF/Q4-D5G18. The effects of other loci were included in a general model by specifying the quantitative traits they influenced as covariates along with age, sex, and an environmental effect. Use of covariate and quantitative trait data in each analysis resulted in respective chi 2 values with 1 df of 38.4, 65.4, and 22.0 to reject the no linkage hypothesis at theta = 0, with respective equivalent lod scores of 8.3, 14.2, and 4.8. Rejection at p < 0.0002 occurred using markers as far away as 20 cM. These loci were not detected when AF alone was analyzed.

Chromosome Mapping↗

Molecular imaging of tumor angiogenesis.

The emergence of angiogenesis as an important target for cancer therapy has led to increased research aimed at understanding the mechanisms underlying the development, maintenance, and destruction of tumor vasculature. Concurrently, molecular imaging technologies have been developed and are being incorporated as integral components of biomedical research due to their ability to noninvasively monitor in vivo molecular events. With the evaluation of numerous anti-angiogenic agents in clinical trials, the adaptation and validation of molecular imaging modalities for monitoring angiogenesis is actively being pursued. The importance of selecting appropriate molecular targets in the study of angiogenesis has become increasingly complex due to the pleiotropy of vascular phenotypes. Furthermore, due to both the relatively low abundance of endothelial cells in tumor tissue and the inherent difficulties of detecting molecular events, molecular imaging of vasculature necessitates continued improvements in achieving higher sensitivity. While several studies have been published that set the groundwork for imaging angiogenesis, much has yet to be accomplished. Various tumor models and transgenic mice provide an excellent resource for developing molecular imaging technologies for the understanding of angiogenesis. This research may play a particularly crucial role in evaluating mechanism and efficacy during pre-clinical testing of anti-angiogenic drugs. Due to practical limitations, however, the implementation of angiogenesis-directed molecular imaging may not extend beyond highly specialized clinical trials. That is, imaging modalities that evaluate angiogenesis at a functional level may prove more appropriate. Despite future technical challenges, molecular imaging will become an important research and clinical tool in evaluating tumor angiogenesis.

Animals↗