Pseudohypoparathyroidism 1b: exclusion of parathyroid hormone and its receptors as candidate disease genes.

Pseudohypoparathyroidism 1b (PHP 1b) is characterized by specific resistance of target tissues to PTH, but no mutations in the PTH/PTH-related peptide (PTHrP) receptor gene have been identified. To investigate the basis for defective PTH signaling, we used polymorphic markers in or near the genes encoding PTH and its receptors to perform linkage analysis between these loci and PHP 1b. Two multiplex PHP 1b families (families M and K) were informative for an intragenic polymorphism in exon 13 of the PTH/PTHrP receptor gene detected by PCR amplification and resolved by denaturing gradient gel electrophoresis. Linkage analysis revealed discordance of the PTH/PTHrP receptor with PHP1b. One PHP 1b kindred (family M) was informative for a intragenic polymorphism in exon 3 of the PTH gene detected by PCR amplification and resolved by denaturing gradient gel electrophoresis. The PTH gene polymorphism segregation was discordant with PHP 1b. Probands from each family had normal PTH genes by direct sequence analysis. In three PHP 1b kindreds, we analyzed simple sequence polymorphisms in three microsatellite markers flanking the PTH type 2 receptor locus located at 2q33. Linkage analysis demonstrated no linkage. In conclusion, neither the PTH gene nor the PTH receptor genes (type 1 and 2) are linked to PHP 1b.

Identification of novel susceptibility loci for inflammatory bowel disease on chromosomes 1p, 3q, and 4q: evidence for epistasis between 1p and IBD1.

The idiopathic inflammatory bowel diseases, Crohn's disease (CD) and ulcerative colitis (UC), are chronic, frequently disabling diseases of the intestines. Segregation analyses, twin concordance, and ethnic differences in familial risks have established that CD and UC are complex, non-Mendelian, related genetic disorders. We performed a genome-wide screen using 377 autosomal markers, on 297 CD, UC, or mixed relative pairs from 174 families, 37% Ashkenazim. We observed evidence for linkage at 3q for all families (multipoint logarithm of the odds score (MLod) = 2.29, P = 5.7 x 10(-4)), with greatest significance for non-Ashkenazim Caucasians (MLod = 3.39, P = 3.92 x 10(-5)), and at chromosome 1p (MLod = 2.65, P = 2.4 x 10(-4)) for all families. In a limited subset of mixed families (containing one member with CD and another with UC), evidence for linkage was observed on chromosome 4q (MLod = 2.76, P = 1.9 x 10(-4)), especially among Ashkenazim. There was confirmatory evidence for a CD locus, overlapping IBD1, in the pericentromeric region of chromosome 16 (MLod = 1.69, P = 2.6 x 10(-3)), particularly among Ashkenazim (MLod = 1.51, P = 7.8 x 10(-3)); however, positive MLod scores were observed over a very broad region of chromosome 16. Furthermore, evidence for epistasis between IBD1 and chromosome 1p was observed. Thirteen additional loci demonstrated nominal (MLod > 1.0, P < 0.016) evidence for linkage. This screen provides strong evidence that there are several major susceptibility loci contributing to the genetic risk for CD and UC.

Twin closeness and co-twin risk for substance use disorders: assessing the impact of the equal environment assumption.

Various environmental variables are hypothesized to operate differentially within identical and fraternal twin pairs. To the extent that these factors are correlated with behavioral outcomes, such as alcohol or drug abuse, traditional twin studies of concordance may be biased. Self-ratings of within-pair emotional closeness, assessed in 169 same-sex twin pairs ascertained through alcohol and drug treatment centers, were used to determine the impact of the twin relationship on concordance for alcohol dependence (N = 130 twin pairs) and other drug abuse and/or dependence (N = 85 twin pairs). In general, identical twin pairs reported significantly closer relationships than fraternal twin pairs, and female twin pairs reported significantly closer relationships than male twin pairs. The data did not indicate an overall effect of closeness on co-twin risk for alcohol dependence. In contrast, closeness was significantly related to co-twin risk for other drug abuse and/or dependence. However, the MZ/DZ concordance difference for other drug abuse and/or dependence remained significant when the effects of within-pair closeness were controlled. Thus, the initial zygosity and sex differences in concordance for substance use disorders cannot be explained solely by differences in twin relationship due to closeness as assessed in this study.

A linkage map of chromosome 6 based on 2 large kindreds segregating bipolar affective disorder.

Twenty-eight markers, both simple sequence repeats (SSRs) and restriction fragment length polymorphisms (RFLPs), were genotyped on members of 2 large pedigrees (OOA, BIP167) segregating bipolar affective disorder. Using the multipoint program "build" of CRIMAP and odds of placement 1000:1, a unique sex-averaged map was generated that spans 227 cM and includes 26 markers. The two other markers were placed on the map with a lower likelihood. The female recombination map is larger than the male recombination map by about 80%. Linkage analysis between the polymorphisms and the disease in the OOA screening pedigree did not result in any significantly positive lod scores nor did a non-parametric, identity-by-descent, method generate any significant p-values. BIP167 was analyzed for allele sharing at the simple sequence repeat loci and significant associations were not found. At present we conclude, that the pedigrees under study do not have a major predisposition gene for bipolar affective disorder on chromosome 6 under the diagnostic and transmission models analyzed by the 2 different methods.

A follow-up report of a genome search for affective disorder predisposition loci in the Old Order Amish.

Progress of a full-genome scan for predisposition loci for affective disorder in the Old Order Amish is reported. LOD-score results have been previously published for 51 loci on chromosomes 1 and 11, collectively. The present report contains results for an additional 367 loci throughout the genome with extensive coverage on chromosomes 1, 2, 3, 4, 6, 7, 9, 10, 13, 14, 18, 19, and 21 (average marker density for these chromosomes = 10.7 cM). Analyses were conducted in a four-stage process: (1) two-point LOD scores were calculated for all loci under a dominant model with reduced penetrance, consistent with results of segregation analyses of these pedigrees; (2) a screen for the sharing of alleles in similarly affected individuals was used to highlight areas potentially important for further analysis; (3) the preceding areas and markers on densely covered chromosomes were analyzed using the affected-pedigree-member (APM) method; and (4) the sharing of extended haplotypes in affected individuals was examined in areas showing apparent clustering of significant allele sharing as assessed by the APM method. Of the 367 markers analyzed, no statistically significant LOD scores resulted. Some degree (P < .05) of allele sharing was found at 74 loci, and 3.8% of all markers analyzed (N = 14) passed more stringent significance criteria suggestive of linkage (P < or = .001 for at least one of the weighting functions). Multilocus APM and detailed exploration of extended haplotype sharing in areas highlighted by the APM analyses provided methods for more informative exploration of potentially suggestive results but did not identify areas clearly involved in the etiology of affective disorder in this population.

Family study and segregation analysis of Tourette syndrome: evidence for a mixed model of inheritance.

To investigate the transmission of Tourette syndrome (TS) and associated disorders within families, complex segregation analysis was performed on family study data obtained from 53 independently ascertained children and adolescents with TS and their 154 first-degree relatives. The results suggest that the susceptibility for TS is conveyed by a major locus in combination with a multifactorial background. Other models of inheritance were definitively rejected, including strictly polygenic models, all single major locus models, and mixed models with dominant and recessive major loci. The frequency of the TS susceptibility allele was estimated to be .01. The major locus accounts for over half of the phenotypic variance for TS, whereas the multifactorial background accounts for approximately 40% of phenotypic variance. Penetrance estimates suggest that all individuals homozygous for the susceptibility allele at the major locus are affected, whereas only 2.2% of males and 0.3% of females heterozygous at the major locus are affected. Of individuals affected with TS, approximately 62% are heterozygous and approximately 38% are homozygous at the major locus. While none of the families had two parents affected with TS, 19% of families had two parents affected with the broader, phenotype, which includes TS, chronic tic disorder, or obsessive-compulsive disorder.

Common genetic mechanisms in alcohol, drug, and mental disorder comorbidity.

Comorbid drug and mental disorders were assessed in 63 monozygotic (MZ) and 67 dizygotic (DZ) twin pairs. DSM-III alcohol dependence was heritable in males when probands had a comorbid DSM-III drug or mental disorder but not when probands had only alcohol dependence. For males, significantly higher cross-MZ than cross-DZ correlations were found between alcohol dependence in probands and certain mental and drug disorders in cotwins. In contrast, females showed higher within-twin than cross-MZ correlations and similar cross-MZ and cross-DZ correlations between alcohol dependence and all mental and drug disorders. These results suggest comorbidity between alcohol and certain drug and mental disorders in males in epidemiological surveys may be due in part to genetic influences.

Two-locus approach of segregation and linkage analysis in the study of complex traits.

A two-locus segregation and linkage-analysis approach was used to characterize the genetic control of a complex trait (Q1) and to localize the genes that have detectable effects. The results suggested that a two-locus Mendelian model fit the data significantly better than a one-locus model. The linkage results based on the most parsimonious two-locus model revealed linkage of Q1 to two areas (MG2 and MG3), while there was less evidence for linkage using one-locus models. Results also suggested that the subphenotypes (Q2 and Q3) provided useful information for further analysis of Q1 using two-locus models.

Initial report of a genome search for the affective disorder predisposition gene in the old order Amish pedigrees: chromosomes 1 and 11.

Family data have suggested that some forms of major affective disorder are genetic. Certain of the Old Order Amish pedigrees have a familial form of the disease. In this report we present the results of genetic analyses under autosomal dominant mode of transmission with reduced penetrance and three different disease hierarchies. The pedigrees were genotyped with 28 markers from chromosome 1 and 23 markers from chromosomes 11. None of the markers result in a significantly positive lod score.

Genomic imprinting and anticipation in idiopathic torsion dystonia.

Idiopathic torsion dystonia (ITD) is a dominantly inherited disorder with variable penetrance and expressivity. Factors affecting the penetrance of the ITD gene have not yet been identified. The present study used four published series of cases to test specific hypotheses regarding factors that could affect the expression of ITD. Among the combined 253 families, transmission of ITD did not depend on either the sex of the affected offspring or that of the transmitting parent. Furthermore, neither the specific type of dystonia manifested, the site at which clinical signs of dystonia first appeared, nor age of onset differed significantly as a function of the gender of the transmitting parent. However, in familial cases of later onset (age > or = 20 years), nearly all involved a transmitting mother. There is evidence for consistency of age of onset within the subset of Jewish families. Although anticipation effects are apparent, sampling bias cannot be ruled out.

Usefulness of twin studies for exploring the etiology of childhood and adolescent psychiatric disorders.

It is estimated that approximately 12% of the individuals under the age of 18 in the United States have a diagnosable mental illness [Institute of Medicine, 1989]; however, only a minority of the etiological research in psychopathology focuses on disorders with childhood onset. The present report demonstrates the usefulness of twin studies in exploring the etiology of childhood and adolescent psychiatric psychopathology and reviews the design, methodology, and results from traditional twin studies of various behavioral disorders. Alternative twin designs are also reviewed in an effort to address the future direction of twin studies in the area of childhood and adolescent psychopathology and to illustrate that twin data have much more to offer the field of psychopathology than merely an initial test to rule in or to rule out a significant genetic contribution to the development of such behaviors.

Similarity in general cognitive ability, creativity, and cognitive style in a sample of adolescent Russian twins.

Data on five tests of general and specific cognitive abilities, cognitive styles, and creativity, obtained from members of 60 identical and 63 fraternal Russian adolescent twin pairs, are presented. All tests are adaptations of standardized instruments widely used outside of the Soviet Union. Identical and fraternal twin correlations for general cognitive ability yielded a lower estimate of heritability (0.29) than generally found in other countries worldwide (0.52) although the twin correlations themselves are fairly comparable to figures from other countries and cultures--0.83 and 0.69 for Russian identical and fraternal twin pairs, respectively, vs 0.86 and 0.60 for non-Russian identical, and fraternal twin pairs. Twin correlations for other cognitive-related abilities assessed were also comparable to correlations obtained outside the Soviet Union with the exception of creativity which yielded higher within-pair resemblance than reported in previous twin studies.

Linkage of bipolar affective disorders to markers on chromosome 11p is excluded in a second lateral extension of Amish pedigree 110.

Linkage between markers on chromosome 11p and bipolar affective disorders can be excluded in a second large lateral extension of the original Amish Pedigree 110. These results, together with previous negative linkage findings, suggest that there is not one single gene on 11p conferring susceptibility for bipolar affective disorders among the Old Order Amish.

Genetic and environmental etiologies of reading disability: A twin study.

Previous twin studies of reading disability employed a comparison of concordance rates in identical and fraternal twin pairs as a test for genetic etiology. Recently, a statistically more powerful multiple regression analysis of twin data has been formulated to assess the importance of genetic factors in the development of reading difficulties. Application of this analysis to twin data from the Colorado Reading Project yields definitive evidence for a genetic etiology. Results from this study suggest that approximately 40 percent of the deficit observed in the disabled readers is due to genetic factors, 35 percent is due to environmental influences shared by members of twin pairs, and about 25 percent is the result of environmental factors unique to the individual and/or error variance.

Evidence for a genetic aetiology in reading disability of twins.

Reading disability (dyslexia) is a major social, educational, and mental health problem. Although estimates of prevalence vary, up to 10-15% of school-age children have severe reading deficits in spite of average intelligence and adequate educational opportunity. That reading disability may have a constitutional basis has long been recognized, and results of twin and family studies suggest that one or more of its forms may be heritable; however, definitive evidence for a genetic aetiology has not been reported. Establishing a heritable basis for reading disability could suggest possible causes, give improved risk estimates, facilitate early diagnosis, and provide validity tests for ostensible subtypes. In this report, we apply a recently developed multiple regression analysis to data collected from a sample of 64 pairs of identical twins and 55 pairs of fraternal twins, in which at least one member of the pairs is reading disabled, and present evidence for a significant genetic aetiology.

Longitudinal stability of cognitive ability from infancy to early childhood: genetic and environmental etiologies.

A path model of genetic and shared family environmental transmission was fitted to general cognitive ability data from 1-, 2-, 3-, and 4-year-old adopted and nonadopted children and their parents in order to assess the etiology of longitudinal stability from infancy to early childhood. Stability across years is moderate and is due mainly to influences not predicted by parental IQ. Results of the present study, in conjunction with those of previous twin studies, suggest substantial genetic stability from infancy and early childhood to adulthood.

Multiple regression analysis of twin data obtained from selected samples.

The multiple regression analysis of twin data in which a cotwin's score is predicted from that of a proband (the member of a twin pair selected because of a deviant score) and the coefficient of relationship provides a powerful test of genetic etiology (DeFries and Fulker: Behav Genet 15:467-473, 1985). Moreover, when an augmented model containing an interaction term is fitted to the same data set, direct estimates of heritability (h2) and the proportion of variance owing to shared environmental influences (c2) are also obtained. In the present paper, the expected partial regression coefficients estimated from these models are derived, and the flexibility of the general approach is illustrated. An extended model is formulated for the analysis of data from combined samples of affected and control twin pairs that yields tests for differential h2 and c2 in the two groups as well as pooled estimates of these parameters. The application of these models is illustrated by an analysis of data from reading-disabled and control twin pairs. Because of the ease, flexibility, and utility of the multiple regression analysis of twin data, it is an appealing alternative to more traditional model-fitting approaches.

Multivariate Familial Analysis of Cognitive Measures in the Colorado Family Reading Study.

Multivariate path analysis is employed to examine the etiologies of variation and covariation of three composite cognitive measures in the Colorado Family Reading Study: reading ability, symbol-processing speed, and spatial/reasoning. Measures of phenotypic assortative and cross-assortative mating are incorporated in a multivariate analysis of familial resemblance within nuclear families. Phenotypic variances and covariances are partitioned into components due to familial (genetic and/or family environmental) influences and to specific, nontransmissible environmental influences in families with a reading-disabled child as well as families with children of normal reading ability. Comparable moderate familial influences are found across family type for all three composites and the phenotypic correlations between traits are largely due to familial influences.