Quantitative models of the genetic transmission of schizophrenia.

Reviews research that has focused on specifying the genetic mechanisms involved in the familial transmission of vulnerability to schizophrenia. The importance of specifying the mechanism and methodological issues involved in genetic modeling are discussed. Models of genetic transmission are described and analyzed, including single major locus models, polygenic models (such as limited loci polygenic models and multifactorial polygenic models), and mixed models. Findings provide little support for the mechanism of single major locus inheritance. Although a mechanism involving 2, 3, or 4 loci cannot be ruled out, there is no compelling support for such models. The multifactorial polygenic model has received the most support and indicates that genetic factors play a greater role than cultural factors in familial transmission. At present, results neither support nor refute a mixed genetic model including both a multifactorial component and a single major locus. Implications of genetic heterogeneity and methodological deficiencies that limit the interpretability of these studies are discussed. (79 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Complex segregation analysis in a sample of consecutive newborns with cleft lip with or without cleft palate in Italy

The mode of inheritance of cleft lip with or without cleft palate (CL/P) has been extensively investigated, but the results are controversial. We report results of complex segregation analysis performed in the families of 636 consecutive newborns with CL/P registered in the northeast Italy and Emilia Romagna congenital malformation registries to test hypotheses regarding CL/P inheritance. The programs POINTER and COMDS have been used. POINTER could not distinguish between alternative genetic models, and only the hypothesis of no familial transmission could be rejected. COMDS results, after inclusion of the severity parameter, rejected the hypotheses of a single major locus and were consistent with the two-locus model with a major dominant locus and at least one modifier locus.     

Molecular mass determination by sedimentation velocity experiments and direct fitting of the concentration profiles

A large English pedigree in which heterocellular hereditary persistence of fetal hemoglobin (HPFH) segregates is described. beta-globin cluster deletions and gamma gene promoter mutations associated with HPFH have been excluded. Of particular importance in this pedigree is the absence of any cosegregating hemoglobinopathy, thus allowing observation of the segregation pattern of this form of HPFH without the complicating effect of a beta-globin gene mutation. Information gained in this study confirms that the extent of elevation of hemoglobin (Hb) F and F cells varies between affected individuals. There are one example of incomplete penetrance and three examples of father-to-son transmission, thus excluding X-linked inheritance. Consistent with previous reports, the most likely mode of inheritance is autosomal codominant. Linkage studies using a beta-globin cluster microsatellite show no evidence of linkage to this chromosomal region implicating the presence of trans-acting regulatory factor(s). We have recently mapped one such locus to the chromosome 6q region in a very large Asian-Indian pedigree. Linkage to chromosome 6q in the English pedigree was excluded, thus indicating the presence of genetic heterogeneity in heterocellular HPFH.     

Convergence of nociceptive and non-nociceptive inputs onto spinal reflex pathways to the tibialis anterior muscle in humans

To investigate whether the familial clustering of cutaneous melanoma is consistent with Mendelian inheritance of a major autosomal gene, maximum likelihood segregation analyses were performed in a population-based sample of 1,912 families ascertained through a proband with melanoma diagnosed in Queensland between 1982 and 1990. Analyses were performed with the S.A.G.E. statistical package, using the REGTL program for a binary trait with a variable age of onset. We sought medical confirmation for all family members reported to have had melanoma, and only medically verified cases among relatives were included in the analyses. The hypothesis of codominant Mendelian inheritance gave a significantly better fit to the data than either dominant or recessive Mendelian inheritance, or environmental transmission. Overall, both Mendelian inheritance of a single major gene, and purely environmental transmission were rejected (P < 0.001). In both the single major gene and environmental models, there was strong evidence of familial dependence in melanoma occurrence (P < 0.001). These results are consistent with reported genetic heterogeneity in melanoma inheritance and suggest that other familial factors, such as pigmentation, skin type, and sun exposure habits, may play an important role in the familial clustering of melanoma.     

Segregation analysis of NIDDM in Caucasian families

Non-insulin-dependent diabetes mellitus (NIDDM) has a substantial genetic component, but the mode of inheritance and the molecular basis are unknown. We have undertaken segregation analysis of NIDDM after studying 247 subjects in 59 Caucasian nuclear pedigrees ascertained without regard to family history of the disorder. The analyses were performed using POINTER and COMDS, which are computer programs which apply statistical models to the data. POINTER analysis was performed defining the phenotype as a presence or absence of hyperglycaemia. Among single locus hypothesis, the analyses rejected a recessive model and favoured a dominant model, but could not statistically show that this fitted better than a mixed model (a single locus against a polygenic background) or a polygenic model. COMDS analysis assumed a continuum of hyperglycaemia from normality to NIDDM, classified family members into a series of diathesis classes with increasing plasma glucose levels and compared the distribution with that found by screening the normal population. This analysis improved the likelihood of a dominant single locus model and suggested a gene frequency of 7.4%. It raised the possibility of a second locus, but cannot identify or exclude a polygenic model. In conclusion, two types of segregation analyses rejected a recessive model and favoured a dominant model of inheritance, although they could not statistically show that this fitted better than the polygenic model. The results raised the possibility of a common dominant gene with incomplete penetrance, but genetic analysis of NIDDM needs to take into account the likelihood of polygenic inheritance with genetic heterogeneity.     

Homozygous parent affected sib pair method for detecting disease predisposing variants: application to insulin dependent diabetes mellitus

For complex genetic diseases involving incomplete penetrance, genetic heterogeneity, and multiple disease genes, it is often difficult to determine the molecular variant(s) responsible for the disease pathogenesis. Linkage and association studies may help identify genetic regions and molecular variants suspected of being directly responsible for disease predisposition or protection, but, especially for complex diseases, they are less useful for determining when a predisposing molecular variant has been identified. In this paper, we expand upon the simple concept that if a genetic factor predisposing to disease has been fully identified, then a parent homozygous for this factor should transmit either of his/her copies at random to any affected children. Closely linked markers are used to determine identity by descent values in affected sib pairs from a parent homozygous for a putative disease predisposing factor. The expected deviation of haplotype sharing from 50%, when not all haplotypes carrying this factor are in fact equally predisposing, has been algebraically determined for a single locus general disease model. Equations to determine expected sharing for multiple disease alleles or multiple disease locus models have been formulated. The recessive case is in practice limiting and therefore can be used to estimate the maximum proportion of putative susceptibility haplotypes which are in fact predisposing to disease when the mode of inheritance of a disease is unknown. This method has been applied to 27 DR3/DR3 parents and 50 DR4/DR4 parents who have at least 2 children affected with insulin dependent diabetes mellitus (IDDM). The transmission of both DR3 and DR4 haplotypes is statistically different from 50% (P < 0.05 and P < 0.001, respectively). An upper estimate for the proportion of DR3 haplotypes associated with a high IDDM susceptibility is 49%, and for DR4 haplotypes 38%. Our results show that the joint presence of non-Asp at DQ beta position 57 and Arg at DQ alpha position 52, which has been proposed as a strong IDDM predisposing factor, is insufficient to explain the HLA component of IDDM predisposition.     

Genetic heterogeneity of autosomal dominant amelogenesis imperfecta demonstrated by its exclusion from the AIH2 region on human chromosome 4Q

Amelogenesis imperfecta (AI) is a group of hereditary enamel defects, characterized by large clinical diversity. On the basis of differences in clinical manifestation and inheritance pattern, 14 different subtypes have been recognized. A locus for autosomal dominant AI (ADAI) of local hypoplastic type was recently mapped to the region between D4S392 and D4S395 on the long arm of chromosome 4. To test whether the chromosome 4 locus is responsible for other forms of AI as well, a linkage study was carried out with 17 families representing at least five clinical forms of ADAI. Admixture tests for heterogeneity performed with the marker D4S2456 gave statistical support for genetic heterogeneity of ADAI with the odds 78:1. Linkage to the ADAI locus on chromosome 4q (AIH2) could only be demonstrated with families expressing the local hypoplastic type, and there was no support for heterogeneity within that group of families. Furthermore, linkage could be excluded for five families with other clinical forms of ADAI. The data therefore demonstrated that ADAI is genetically heterogeneous, and that at least two loci for it exist.     

Mapping of both autosomal recessive and dominant variants of pseudoxanthoma elasticum to chromosome 16p13.1

Pseudoxanthoma elasticum (PXE) is a classic inherited disorder of the elastic tissue characterized by progressive calcification of elastic fibers with a pathognomonic histological appearance. The clinical manifestations of PXE typically involve the skin, the eye and the cardiovascular system, resulting in skin lesions, decreased vision and vascular disease. Clinically, a more common autosomal recessive and a less common autosomal dominant pattern of inheritance, with high penetrance, have been described; the estimated prevalence of the disease is 1 in 70,000-100,000. Previous failure to link the disease to any of several candidate genes prompted us to conduct a genome-wide screen on a collection of 38 families with two or more affected siblings, using allele sharing algorithms. Excess allele sharing was found on the short arm of chromosome 16 and confirmed by conventional linkage analysis, localizing the disease gene under a recessive model with a maximum two point lod score of 21.27 on chromosome 16p13.1, an area so far devoid of any obvious candidate genes. Under a dominant transmission pattern linkage with a maximum two point lod score of 14.53 was observed to the same region. Linkage heterogeneity analysis predicted the presence of allelic heterogeneity with different variants of a single gene that resides in this chromosomal region accounting for recessive and dominant forms of PXE.     

Familial Mondini dysplasia

OBJECTIVES/HYPOTHESIS: To determine the mode of inheritance of familial nonsyndromic Mondini dysplasia. Study Design: Correlative clinical genetic analysis of a single kindred. METHODS: Clinical history, physical examination, audiologic analysis, computed tomography of the temporal bones, and cytogenetic analysis. RESULTS: The male proband, three affected sisters, and an affected brother are offspring of unaffected parents. The mother and an unaffected brother have audiologic findings suggestive of heterozygous carrier status for a recessive hearing loss gene. CONCLUSIONS: Pedigree analysis indicates autosomal recessive inheritance in this family. The observed inheritance and clinical, audiologic, and radiologic findings are different from those previously described for another family with nonsyndromic Mondini dysplasia. The phenotype in this study family therefore represents a distinct subtype, indicating clinical and genetic heterogeneity of this disorder. This information should facilitate future molecular linkage analyses and genetic counselling of patients with inner ear malformations.     

Thalidomide in the treatment of the mucocutaneous lesions of the Beh?et syndrome. A randomized, double-blind, placebo-controlled trial

Mood disorders are known to cluster within families, but the mode of transmission remains largely unknown. The purpose of our analysis was to determine whether selection of a sample that was homogeneous in its response to an antidepressant provided stronger evidence for a single major locus. Complex segregation analysis was applied to a sample of 171 Italian families of bipolar and unipolar probands that were responsive to the antidepressant fluvoxamine. We used regressive logistic analyses to determine the best fit from among environmental, arbitrary Mendelian, dominant, recessive and additive models. For the 171 affective families with probands that were responsive to the antidepressant fluvoxamine, a Mendelian model of inheritance was rejected. When considering 68 families of bipolar probands, the best fit was obtained for a Mendelian dominant model of transmission. The identification of a Mendelian mode of transmission in bipolar subjects who were selected according to their response to fluvoxamine supports the use of a pharmacological criterion as a tool for identifying true genetic disorders.     

Is pseudoexfoliation syndrome inherited? A review of genetic and nongenetic factors and a new observation

Pseudoexfoliation (PEX) syndrome is the commonest identifiable cause of open-angle glaucoma worldwide. PEX is characterized clinically by small whitish deposits of fibrillar-granular material in the anterior segment of the eye. Despite its prevalence and potential for ophthalmic morbidity, surprisingly little is known about the etiology and pathogenesis of PEX. This article reviews the literature and presents evidence regarding genetic and nongenetic arguments for the etiology of pseudoexfoliation. Lines of evidence that support a genetic basis for PEX include transmission in two-generation families, twin studies, an increased risk of PEX in relatives of affected patients, and HLA studies. Nearly all pedigrees in the literature, and our own experience with PEX families in Iceland and Canada, suggest maternal transmission, raising the possibilities of mitochondrial inheritance, X-linked inheritance, and autosomal inheritance with genomic imprinting. A number of nongenetic factors have also been evaluated for their possible implication in the development of PEX. These include ultraviolet light, autoimmunity, slow virus infection, and trauma. It is possible that a combination of genetic and nongenetic factors may be involved in the etiology and pathogenesis of PEX, i.e. it may be a multifactorial disorder. Further studies with larger numbers of patients are needed to delineate more clearly the contribution of genetic (nuclear DNA, mitochondrial DNA or both) and nongenetic factors to the development of pseudoexfoliation syndrome and pseudoexfoliation glaucoma.     

No evidence for significant linkage between bipolar affective disorder and chromosome 18 pericentromeric markers in a large series of multiplex extended pedigrees

Bipolar affective disorder (BP) is a major neuropsychiatric disorder with high heritability and complex inheritance. Previously reported linkage between BP and DNA markers in the pericentromeric region of chromosome 18, with a parent-of-origin effect (linkage was present in pedigrees with paternal transmission and absent in pedigrees with exclusive maternal inheritance), has been a focus of interest in human genetics. We reexamined the evidence in one of the largest samples reported to date (1,013 genotyped individuals in 53 unilineal multiplex pedigrees), using 10 highly polymorphic markers and a range of parametric and nonparametric analyses. There was no evidence for significant linkage between BP and chromosome 18 pericentromeric markers in the sample as a whole, nor was there evidence for significant parent-of-origin effect (pedigrees with paternal transmission were not differentially linked to the implicated chromosomal region). Two-point LOD scores and single-locus sib-pair results gave some support for suggestive linkage, but this was not substantiated by multilocus analysis, and the results were further tempered by multiple test effects. We conclude that there is no compelling evidence for linkage between BP and chromosome 18 pericentromeric markers in this sample.     

Tetracaine-lidocaine-phenylephrine topical anesthesia compared with lidocaine infiltration during repair of mucous membrane lacerations in children

When a rigorous methodological approach is utilized, a substantial majority of recent studies provide evidence for the familial transmission of schizophrenia. Although the absolute rates of schizophrenia among relatives of schizophrenics tend to be lower than those reported in the earlier studies due to the restrictiveness of contemporary definitions of schizophrenia, the risk to relatives compared to that of controls has remained quite consistent. This observation that relatives of schizophrenics have an elevated risk for schizophrenia compared to controls is consistent with theories of both genetic and environmental transmission. Twin studies of schizophrenia have consistently reported greater concordance rates for monozygotic than dizygotic twins. Although this indicates the importance of genetic factors, the less than 100% concordance for monozygotic twins observed in every study indicates that nongenetic factors also play a role in the etiology of schizophrenia. Further, adoption studies offer an opportunity to unconfound genes and environment. The findings of adoption studies confirm that there are genetic components for schizophrenia. Even though we have shown that family, twin, and adoption studies have provided strong evidence for the role of genetic factors in schizophrenia, the mode of transmission remains unclear. The results of mathematical modeling studies do not support the single gene model. There is somewhat more support for the multifactorial polygenic model, but the model has also been rejected in several studies. Thus, the pattern of inheritance of schizophrenia has eluded an unambiguous characterization. Genetic linkage analysis promised to clarify the mechanisms of transmission, but early positive reports were subsequently overturned and, to date, there are no consistently replicated positive linkage findings for schizophrenia. There is now a world-wide search for the location of the genes on specific chromosomes which are responsible for schizophrenia. The clinical implications of current work to the future of locating a schizophrenic gene or genes will be discussed.     

The genetics of vitiligo in Korean patients

BACKGROUND: Vitiligo is a common disorder whose exact cause is unknown, but genetic factors are thought to be involved. We analyzed 120 Korean proband families to clarify which genetic factors are involved in the pathogenesis of vitiligo in Korean patients. METHODS: The genetics of vitiligo were analyzed in 120 Korean proband families out of 1030 vitiligo patients. Each family was analyzed through a proband afflicted with vitiligo. RESULTS: In 51 (42.5%) of 120 proband families, at least one first-degree relative of the proband had vitiligo. The incidence of those affected among 1755 relatives (first-, second-, and third-degree) was found to be 8.0+/-0.6%. There was a statistically significant departure for segregation analysis which was inconsistent with inheritance as an autosomal or X-linked locus model. On the basis of our results, the inheritance pattern of vitiligo is more likely to tend toward the model of multifactorial inheritance. The threshold trait among first-degree relatives (7.2%) appeared to tend more toward the square root of the frequency in the general population (10%) than towards those of dominant (50%) or recessive (25%) models. CONCLUSIONS: These results indicate that there are certain genetic factors involved in the etiology of vitiligo, and that vitiligo seems to have a polygenic nature.     

Heterogeneity in Klippel-Feil syndrome: a new classification

BACKGROUND: Klippel-Feil syndrome (KFS) is characterised by congenital vertebral fusion of the cervical spine and a wide spectrum of associated anomalies. KFS has often been considered a sporadic syndrome. However, since the publication of the original KFS classification early this century, a number of KFS families have indicated heterogeneity complicated by a broad range of variable expression. OBJECTIVE: The two major objectives of this study were (1) to identify differences and similarities in the postnatal appearance, morphology, position and inheritance of vertebral fusions within and between KFS families and (2) to establish a new KFS classification focussed on KFS aetiology. MATERIALS AND METHODS: Vertebral fusions were assessed via spinal radiography. Chromosomal karyotypes were performed using routine cytogenetics. RESULTS: The medical histories of three KFS families are presented. The postnatal time, position and appearance of vertebral fusions, associated anomalies and mode of inheritance were different for the three KFS families. Four classes of KFS are described in a comprehensive classification table that allays much of the uncertainty arising from KFS heterogeneity and variable expression. CONCLUSION: We have described four different KFS classes (KF1-4) within a comprehensive classification that addresses KFS genetic heterogeneity. The position of vertebral fusions in the cervical spine and their incidence within affected families are delineating features of KFS.     

Determination of indole-3-pyruvic acid levels in Arabidopsis thaliana by gas chromatography-selected ion monitoring-mass spectrometry

Primary systemic carnitine deficiency (SCD) is a rare hereditary disorder transmitted by an autosomal recessive mode of inheritance. The disorder includes cardiomyopathy, muscle weakness, hypoketotic coma with hypoglycemia, and hyperammonemia. In this study, we conducted a linkage analysis of a Japanese SCD family with a proband-a 9-year-old girl-and 26 members. The serum and urinary carnitine levels were determined for all members. The entire genome was searched for linkage to the gene locus for SCD, by use of a total of approximately 300 polymorphic markers located approximately 15-20 cM apart. In the family, there were two significantly different phenotypes, in terms of serum free-carnitine levels: low serum free-carnitine level (29.5+/-5.0 microM; n=14) and normal serum free-carnitine level (46.8+/-6.2 microM; n=12). There was no correlation of urinary free-carnitine levels with the low serum-level phenotype (putative heterozygote), but in normal phenotypes (wild type) urinary levels decreased as the serum levels decreased; renal resorption of free carnitine appeared to be complete in wild-type individuals, when the serum free-carnitine level was <36 microM. Linkage analysis using an autosomal dominant mode of inheritance of heterozygosity revealed a tight linkage between the disease allele and D5S436 on chromosome 5q, with a two-point LOD score of 4.98 and a multipoint LOD score of 5.52. The haplotype analysis revealed that the responsible genetic locus lies between D5S658 and D5S434, which we named the "SCD" locus. This region was syntenic with the jvs locus, which is responsible for murine SCD. Phylogenic conversion of the SCD locus strongly suggests involvement of a single gene, in human SCD.     

Nonsyndromic cleft lip with or without cleft palate: evidence of linkage to BCL3 in 17 multigenerational families

Nonsyndromic cleft lip with or without cleft palate (CL/P) is a common craniofacial developmental defect. Recent segregation analyses have suggested that major genes play a role in the etiology of CL/P. Linkage to 22 candidate genes was tested in 11 multigenerational families with CL/P, and 21 of these candidates were excluded. APOC2, 19q13.1, which is linked to the proto-oncogene BCL3, gave suggestive evidence for linkage to CL/P. The study was expanded to include a total of 39 multigenerational CL/P families. Linkage was tested in all families, using an anonymous marker, D19S178, and intragenic markers in BCL3 and APOC2. Linkage was tested under two models, autosomal dominant with reduced penetrance and affecteds only. Homogeneity testing on the two-point data gave evidence of heterogeneity at APOC2 under the affecteds-only model. Both models showed evidence of heterogeneity, with 43% of families linked at zero recombination to BCL3 when marker data from BCL3 and APOC2 were included. A maximum multipoint LOD score of 7.00 at BCL3 was found among the 17 families that had posterior probabilities > = 50% in favor of linkage. The transmission disequilibrium test provided additional evidence for linkage with the 3 allele of BCL3 more often transmitted to affected children. These results suggest that BCL3, or a nearby gene, plays a role in the etiology of CL/P in some families.     

A comprehensive linkage analysis of chromosome 21q22 supports prior evidence for a putative bipolar affective disorder locus

Previously, we demonstrated evidence of linkage to bipolar affective disorder (BP) in a single large, multigenerational family with a LOD score of 3.41 at the PFKL locus on chromosome 21q22.3. Additional families showed little support for linkage to PFKL under homogeneity or heterogeneity, in that study. We have expanded on that analysis, with 31 microsatellite markers at an average marker spacing of 相似文献   

Features of the type of inheritance of myotonic dystrophy

The characteristic features of the genetics of myotonic dystrophy (MD) in the Bulgarian population were studied. Seventy-nine pedigrees were analyzed, comprising a total of 119 patients with MD. The following characteristic features of the MD genetics were revealed: (1) Different families exhibited different patterns of the disease transmission, including vertical (as in the autosomal dominant mode of inheritance), horizontal (as in the autosomal recessive mode of inheritance), and mixed (the horizontal transmission for the first generations and the vertical transmission for the subsequent ones); (2) All studied pedigrees were traced back to clinically healthy ancestors; (3) The symptoms of MD exhibited in anticipation, as well as a clinical heterogeneity in sibships with respect to the severity of the disease. The characteristic features of the revealed mode of inheritance may be explained by dynamic mutations.     

Hereditary deafness in Turkey. Initial results

The authors describe a study in progress to identify Turkish families with hereditary hearing loss and isolate possible responsible disease genes. Due to extreme genetic heterogeneity and limited audiological differentiation of hereditary hearing loss, it is necessary to identify large or small families from genetic isolates to locate loci responsible for hearing loss on a chromosome. To accomplish this goal, the medical records of 3800 children were examined at the ENT Clinic of Ege University between 1975 and 1994. All were suspected of having various hearing impairments. Additionally, students from two schools for the hearing impaired in Izmir and Eskisehir, Turkey were examined. To date, 16 families with syndromal deafness and 55 families with non-syndromal hereditary hearing loss involving two or more affected individuals have been identified and categorized according to the mode of inheritance. The majority (66%) of the non-syndromal families showed an autosomal recessive pattern, 29% an autosomal dominant inheritance and 5% an X-linked mode of inheritance. In the study presented there has been a predominance of affected males versus females and the consanguinity rate was 22%.