Reproductive Risk Estimation Calculator for Balanced Translocation Carriers.

Balanced translocation carriers experience elevated reproductive risks, including pregnancy loss and children with anomalies due to generating chromosomally unbalanced gametes. While understanding the likelihood of producing unbalanced conceptuses is critical for individuals to make reproductive decisions, risk estimates are difficult to obtain as most balanced translocations are unique. To improve reproductive risk estimates, Drs. Trunca and Mendell created models based on a logistic regression analysis of a dataset of over 6000 individuals from over 1000 translocation families. While risk assessments using these models have been offered as a free service for years, this protocol aims to create a sustainable model for genetics professionals to obtain risk estimates for their patients directly. This protocol guides the user through collecting clinical information, using a risk-generating Java program based on the models, and interpreting the program outputs. A practice tutorial is provided to ensure competency in interpretation prior to use. © 2022 Wiley Periodicals LLC. Basic Protocol 1: Estimation of reproductive risks for balanced translocation carriers Basic Protocol 2: Practical examples of typical patient encounters with instructive interpretations.

Comparison of putative intermediate phenotypes in schizophrenia patients with and without obsessive-compulsive disorder: examining evidence for the schizo-obsessive subtype.

Obsessive-compulsive symptoms or obsessive-compulsive disorder (OCD) is estimated to occur in up to 30% of patients with schizophrenia. Whether this subgroup of patients is cognitively, affectively, or physiologically distinct remains unclear. 204 schizophrenia patients, 15 who also met criteria for a diagnosis of OCD, and 147 healthy controls were examined on several intermediate phenotypes. The patient groups did not differ from each other except that the co-morbid group exhibited an elevated rate of eye-tracking dysfunction. Results suggest that OCD-co-morbid patients did not comprise a distinct subgroup based on the measures studied here, although systematic assessment of larger cohorts is warranted.

The effects of perceptual encoding on the magnitude of object working memory impairment in schizophrenia.

Deficits in the visual working memory (WM) system have been consistently reported in schizophrenia patients, but the relative contribution of initial perceptual encoding to these deficits remains unsettled. We assessed the role of visual perceptual encoding on performance on an object WM task. Schizophrenia patients (N=37) and nonpsychiatric control subjects (N=33) were tested on an object WM task involving three delay periods: 200 ms, 3s, and 10s. Schizophrenia patients performed significantly less accurately than controls on all three conditions. However, after controlling for the effect of perceptual encoding (accuracy on the 200 ms delay condition) on performance in the two memory load conditions, schizophrenia patients demonstrated intact WM in the 3s delay condition, and showed a weak trend for decreased accuracy on the 10s delay compared with controls. Analysis of individual differences in pattern of performance revealed that a distinct subgroup of poor encoder patients had a significantly greater reduction in accuracy at 3s than the other patient subgroups and controls. In contrast, among schizophrenia patients who performed poorly on the 10s delay, accuracy was equivalently reduced independent of encoding ability. WM deficits in controls were independent of encoding ability at both delay intervals. These results indicate that encoding ability titrates the magnitude of WM impairment in schizophrenia patients but not in controls, and that heterogeneity has to be taken into account to correctly estimate the effects of perceptual encoding on visual object WM deficits in schizophrenia.

Necessary and sufficient conditions for equality of sibling and parent-offspring risk of a disease endophenotype in case families.

A large number of linkage and association studies of complex diseases focus on analysis of a more common or more easily measured disease endophenotype. The motivation for this approach is that there is a pleiotropic locus common to both the disease and the endophenotype and that this locus is a major genetic determinant of the endophenotype. In this paper, we determine the conditions under which the risk of the endophenotype in siblings of affected probands with disease equals the risk of the endophenotype in the offspring (parents) of affected parents (offspring) with disease. In doing so we prove that this equality holds if and only if the penetrance of either the endophenotype or the disease (but not necessarily both) is additive.

Patients' sex and emotional support as predictors of death and clinical deterioration in the waiting for a new heart study: results from the 1-year follow-up.

CONTEXT: Little is known about the role of patient's sex and emotional support in the prognosis of heart transplant candidates. OBJECTIVE: To examine patient's sex and emotional support as predictors of outcomes in the Waiting for a New Heart Study. DESIGN, SETTING, AND PARTICIPANTS: The Waiting for a New Heart Study is a prospective observational study of 318 patients (18% female) newly added to the waiting list for a heart transplant. Demographic, medical, psychosocial characteristics (including social support [ENRICHD Social Support Index; high vs. low support]) were assessed at the time of wait-listing. Main Outcomes-Time until death/delisting due to deteriorated tealth, considering competing outcomes (e.g., transplantation) during the first 12 months after wait-listing were analyzed via cause-specific Cox proportional hazard models. RESULTS: By 12 months, 32 men (12%) and 10 women (17%) had died/deteriorated. Medical risk was comparable across sexes. More men than women reported low emotional support (20.4% vs. 8.6%) and being a past or current smoker (80.4% vs. 56.9%). More women than men had low vocational level (93.1% vs. 69.6%; all P values < .05). With medical risk and other confounding variables controlled for, female sex significantly increased risk of death/deterioration (hazard ratio, 2.30; 95% confidence interval, 1.04-5.12; P = .04); low emotional support further tended to increase the risk for this outcome (P = .07). As none of the 5 women with low emotional support had reached this end point, analyses were performed in the male sample and revealed that men with low emotional support were more than twice as likely to die/deteriorate than were men with high support (hazard ratio, 2.23; 95% confidence interval, 1.04-4.82; P = .04). CONCLUSION: Women had worse survival while awaiting a heart transplant than men had, independent of confounding variables. Even though emotional support may be an important buffer for men, protective factors for women warrant further investigation with larger samples and/or longer follow-ups.

Principal components ancestry adjustment for Genetic Analysis Workshop 17 data.

Statistical tests on rare variant data may well have type I error rates that differ from their nominal levels. Here, we use the Genetic Analysis Workshop 17 data to estimate type I error rates and powers of three models for identifying rare variants associated with a phenotype: (1) by using the number of minor alleles, age, and smoking status as predictor variables; (2) by using the number of minor alleles, age, smoking status, and the identity of the population of the subject as predictor variables; and (3) by using the number of minor alleles, age, smoking status, and ancestry adjustment using 10 principal component scores. We studied both quantitative phenotype and a dichotomized phenotype. The model with principal component adjustment has type I error rates that are closer to the nominal level of significance of 0.05 for single-nucleotide polymorphisms (SNPs) in noncausal genes for the selected phenotype than the model directly adjusting for population. The principal component adjustment model type I error rates are also closer to the nominal level of 0.05 for noncausal SNPs located in causal genes for the phenotype. The power for causal SNPs with the principal component adjustment model is comparable to the power of the other methods. The power using the underlying quantitative phenotype is greater than the power using the dichotomized phenotype.

Parent-child DRD4 genotype as a potential biomarker for oppositional, anxiety, and repetitive behaviors in children with autism spectrum disorder.

The primary objective of the present study was to examine whether a combination of parent-child DRD4 genotypes results in more informative biomarkers of oppositional, separation anxiety, and repetitive behaviors in children with autism spectrum disorder (ASD). Based on prior research indicating the 7-repeat allele as a potential risk variant, participants were sorted into one of four combinations of parent-child genotypes. Owing to the possibility of parent-of-origin effects, analyses were conducted separately for mother-child (MC) and father-child (FC) dyads. Mothers completed a validated DSM-IV-referenced rating scale. Partial eta-squared (ηp(2)) was used to determine the magnitude of group differences: 0.01-0.06=small, 0.06-0.14=moderate, and >0.14=large. Analyses indicated that children in MC dyads with matched genotypes had the least (7-/7-) and most (7+/7+) severe mother-rated oppositional-defiant (ηp(2)=0.11) and separation anxiety (ηp(2)=0.19) symptoms. Conversely, youths in FC dyads with matched genotypes had the least (7-/7-) and most (7+/7+) severe obsessive-compulsive behaviors (ηp(2)=0.19) and tics (ηp(2)=0.18). Youths whose parents were both noncarriers had less severe tics than peers with at least one parental carrier, and the effect size was large (ηp(2)=0.16). There was little evidence that noncarrier children were rated more severely by mothers who were carriers versus noncarriers. Transmission Disequilibrium Test analyses provided preliminary evidence for undertransmission of the 2-repeat allele in youths with more severe tics (p=0.02). Parent genotype may be helpful in constructing prognostic biomarkers for behavioral disturbances in ASD; however, findings are tentative pending replication with larger, independent samples.

Little genetic differentiation as assessed by uniparental markers in the presence of substantial language variation in peoples of the Cross River region of Nigeria.

BACKGROUND: The Cross River region in Nigeria is an extremely diverse area linguistically with over 60 distinct languages still spoken today. It is also a region of great historical importance, being a) adjacent to the likely homeland from which Bantu-speaking people migrated across most of sub-Saharan Africa 3000-5000 years ago and b) the location of Calabar, one of the largest centres during the Atlantic slave trade. Over 1000 DNA samples from 24 clans representing speakers of the six most prominent languages in the region were collected and typed for Y-chromosome (SNPs and microsatellites) and mtDNA markers (Hypervariable Segment 1) in order to examine whether there has been substantial gene flow between groups speaking different languages in the region. In addition the Cross River region was analysed in the context of a larger geographical scale by comparison to bordering Igbo speaking groups as well as neighbouring Cameroon populations and more distant Ghanaian communities. RESULTS: The Cross River region was shown to be extremely homogenous for both Y-chromosome and mtDNA markers with language spoken having no noticeable effect on the genetic structure of the region, consistent with estimates of inter-language gene flow of 10% per generation based on sociological data. However the groups in the region could clearly be differentiated from others in Cameroon and Ghana (and to a lesser extent Igbo populations). Significant correlations between genetic distance and both geographic and linguistic distance were observed at this larger scale. CONCLUSIONS: Previous studies have found significant correlations between genetic variation and language in Africa over large geographic distances, often across language families. However the broad sampling strategies of these datasets have limited their utility for understanding the relationship within language families. This is the first study to show that at very fine geographic/linguistic scales language differences can be maintained in the presence of substantial gene flow over an extended period of time and demonstrates the value of dense sampling strategies and having DNA of known and detailed provenance, a practice that is generally rare when investigating sub-Saharan African demographic processes using genetic data.

The Genetic Basis of Thought Disorder and Language and Communication Disturbances in Schizophrenia.

Thought disorder as well as language and communication disturbances are associated with schizophrenia and are over-represented in clinically unaffected relatives of schizophrenics. All three kinds of dysfunction involve some element of deviant verbalizations, most notably, semantic anomalies. Of particular importance, thought disorder characterized primarily by deviant verbalizations has a higher recurrence in relatives of schizophrenic patients than schizophrenia itself. These findings suggest that deviant verbalizations may be more penetrant expressions of schizophrenia susceptibility genes than schizophrenia. This paper reviews the evidence documenting the presence of thought, language and communication disorders in schizophrenic patients and in their first-degree relatives. This familial aggregation potentially implicates genetic factors in the etiology of thought disorder, language anomalies, and communication disturbances in schizophrenia families. We also present two examples of ways in which thought, language and communication disorders can enrich genetic studies, including those involving schizophrenia.

Tailoring the definition of the clinical schizophrenia phenotype in linkage studies.

The delineation of schizophrenia-related symptomatology is critical to informative clinical phenotyping in linkage studies. A minority of first-degree relatives of schizophrenia and schizoaffective probands (RelSZSA) qualifies for a clinical diagnosis in the schizophrenia spectrum. Schizotypal personality disorder (SPD) is a key component of this spectrum, largely because of its relatively specific familial aggregation in relatives. The criteria for SPD were not developed for the purpose of identifying RelSZSA, however, and SPD is not a homogeneous clinical disorder, potentially introducing false positives and false negatives into affectedness classifications. In this study we used logistic regression (LR) to identify the combination of clinical signs and symptoms that maximized the discrimination between nonpsychotic first-degree RelSZSA (n=241) and controls (n=161). Three variables contributed significantly to optimizing this distinction: no close friends or confidants other than family members, social isolation and irritability. The combination of deviant LR scores and schizophrenia-spectrum psychotic disorders had greater sensitivity for identifying RelSZSA, 23.7%, than SPD and schizophrenia-spectrum psychotic disorders, 16%. Importantly, the diagnosis of SPD and deviant LR scores were not significantly correlated. Most individuals with deviant LR scores did not meet criteria for a diagnosis of SPD and only a minority of those who were diagnosed with SPD had deviant LR scores. Since misclassification of gene carriers as non-gene carriers in linkage analyses increases the risk of false negatives, it may be advantageous to tailor the definition of the clinical phenotype to those aspects of social-interpersonal dysfunction that optimize the discrimination of RelSZSA from controls.

Reinforcement ambiguity and novelty do not account for transitive inference deficits in schizophrenia.

The capacity for transitive inference (TI), a form of relational memory organization, is impaired in schizophrenia patients. In order to disambiguate deficits in TI from the effects of ambiguous reinforcement history and novelty, 28 schizophrenia and 20 nonpsychiatric control subjects were tested on newly developed TI and non-TI tasks that were matched on these 2 variables. Schizophrenia patients performed significantly worse than controls on the TI task but were able to make equivalently difficult nontransitive judgments as well as controls. Neither novelty nor reinforcement ambiguity accounted for the selective deficit of the patients on the TI task. These findings implicate a disturbance in relational memory organization, likely subserved by hippocampal dysfunction, in the pathophysiology of schizophrenia.

Growth mixture modeling as an exploratory analysis tool in longitudinal quantitative trait loci analysis.

We examined the properties of growth mixture modeling in finding longitudinal quantitative trait loci in a genome-wide association study. Two software packages are commonly used in these analyses: Mplus and the SAS TRAJ procedure. We analyzed the 200 replicates of the simulated data with these programs using three tests: the likelihood-ratio test statistic, a direct test of genetic model coefficients, and the chi-square test classifying subjects based on the trajectory model's posterior Bayesian probability. The Mplus program was not effective in this application due to its computational demands. The distributions of these tests applied to genes not related to the trait were sensitive to departures from Hardy-Weinberg equilibrium. The likelihood-ratio test statistic was not usable in this application because its distribution was far from the expected asymptotic distributions when applied to markers with no genetic relation to the quantitative trait. The other two tests were satisfactory. Power was still substantial when we used markers near the gene rather than the gene itself. That is, growth mixture modeling may be useful in genome-wide association studies. For markers near the actual gene, there was somewhat greater power for the direct test of the coefficients and lesser power for the posterior Bayesian probability chi-square test.

Family-based analysis of a myocardial infarction endophenotype: comparison of sampling designs.

The power of linkage analysis of a quantitative disease endophenotype was compared for the following family selection designs: 1) Random samples: randomly chosen nuclear families, 2) "coronary artery calcification (CAC)" samples: selection of each nuclear family through a proband with abnormally high levels of the simulated quantitative endophenotype, CAC, and (3) "MI" samples: selection of each nuclear family through a disease affected proband, in this case a proband who had been simulated to have a myocardial infarction (MI) event.We assessed the power to detect linkage to five loci (two pairs of epistatic loci and one locus with an over-dominant allele) that were modeled as determinants of the simulated CAC levels. We did this using a Haseman-Elston regression-based linkage analysis of the adjusted CAC levels that considered each locus separately and then used a multiple regression extension of the Haseman-Elston method in which we considered the allele sharing at two true epistatic loci simultaneously and their interaction as possible factors related to the squared sibpair differences in adjusted CAC.Based on comparison of the mean square root of the LOD scores, there was no one sampling design that resulted in consistently greater power for these five loci. That is, we observed significant locus-by-sampling-design interaction (p < 0.0001). We noted however, that the largest average score was observed for the epistasis between tau3 and tau4 (mean > 1.8, SE = 0.06) in the MI-selected samples and the CAC-selected samples.

Schizophrenia patients show deficits in shifts of attention to different levels of global-local stimuli: evidence for magnocellular dysfunction.

Abnormalities of attention and visual perception are well documented in schizophrenia. The global-local task is a measure of attention and perceptual organization that utilizes visual stimuli comprised of large letters (global level) made up of smaller letters (local level). Subjects identify target letters appearing at either the global or local level of the stimulus. In this study, we used a version of the global-local task specifically designed to examine lateralized hemispheric processing and attention shifting in 30 schizophrenia patients and 24 normal controls. Global-local stimuli were presented in couplets (consecutive pairs). Reaction time for the second target in a couplet was compared under conditions in which the target remained at the same level (global-global, local-local) and when the target changed levels (global-local, local-global). Level-specific priming (ie, global to global and local to local) and the local-to-global level shift were similar in both groups. Schizophrenia patients were significantly slower, however, shifting attention from the global to the local level. These results implicate an impairment in shifting attentional resources from predominantly right lateralized magnocellular/dorsal stream processing of global targets to predominantly left lateralized parvocellular/ventral stream processing of local targets. Local interference effects in global processing provide further support for impaired magnocellular processing in schizophrenia patients.

Sex-Specific Genetic Data Support One of Two Alternative Versions of the Foundation of the Ruling Dynasty of the Nso' in Cameroon.

Sex-specific genetic data favor a specific variant of the oral history of the kingdom of Nso' (a Grassfields city-state in Cameroon) in which the royal family traces its descent from a founding ancestress who married into an autochthonous hunter-gatherer group. The distributions of Y chromosome and mitochondrial DNA variation in the Nso' in general and in the ruling dynasty in particular are consistent with specific Nso' marriage practices, suggesting strict conservation of the royal social class along agnatic lines. This study demonstrates the efficacy of using genetics to augment other sources of information (e.g., oral histories, archaeology, and linguistics) when seeking to recover the histories of African peoples.

Does performance on the standard antisaccade task meet the co-familiality criterion for an endophenotype?

The "co-familiality" criterion for an endophenotype has two requirements: (1) clinically unaffected relatives as a group should show both a shift in mean performance and an increase in variance compared with controls; (2) performance scores should be heritable. Performance on the antisaccade task is one of several candidate endophenotypes for schizophrenia. In this paper we examine whether the various measures of performance on the standard version of the antisaccade task meet the co-familiality criterion for an endophenotype. The three measures of performance-reflexive saccade errors, latency of correct antisaccades, and gain-show a wide range of effect sizes and variance ratios as well as evidence of significant or near significant heterogeneity. The estimated mean effect sizes [Cohen's d: error rate: 0.34 (SD: 0.29); latency: 0.33 (SD: 0.30); gain: 0.54 (SD: 0.38)] are significantly greater than 0, but the magnitude of the departures from 0 is relatively small, corresponding to modest effect sizes. The width of the 95% confidence intervals for the estimated effect sizes (error rate: 0.2-0.49; latency: 0.17-0.50; gain: 0.23-0.85) and the coefficients of variation in effect sizes (error rate: 85.3%; latency: 90.9%; gain: 68.4%) reflect heterogeneity in effect sizes. The effect sizes for error rate showed statistically significant heterogeneity and those for latency (P=.07) and gain (P=.09) showed a trend toward heterogeneity. These results indicate that the effect sizes are not consistent with a single mean and that the average effect size may be a biased estimate of the magnitude of differences in performance between relatives of schizophrenics and controls. Relatives of schizophrenics show a small but significant increase in variance in error rate, but the confidence interval is broad, perhaps reflecting the heterogeneity in effect size. The variance ratios for latency and gain did not differ in relatives of schizophrenics and controls. Performance, as measured by error rate, is moderately heritable. The data do not provide compelling support for a consistent shift in mean or variance in relatives of schizophrenia patients compared with nonpsychiatric controls, both of which are required for a major gene involved in co-familial transmission. This set of findings suggests that although intra-familial resemblance in antisaccade performance is due in part to genetic factors, it may not be related to a schizophrenia genotype. Based on the current literature, it would be premature to conclude that any of the measures of antisaccade performance unambiguously meets the co-familiality criterion for an endophenotype.

The potentially deleterious functional variant flavin-containing monooxygenase 2*1 is at high frequency throughout sub-Saharan Africa.

BACKGROUND: The drug-metabolizing enzyme flavin-containing monooxygenase 2 (FMO2) is the predominant FMO isoform present in the lung of most mammals, including non-human primates. All Europeans and Asians tested have been shown to be homozygous for a non-functional variant, FMO2*2A, which contains a premature stop codon due to a single-nucleotide change in exon 9 (g.23238C>T). The ancestral allele, FMO2*1, encodes a functionally active protein and has been found in African-Americans (26%) and Hispanics (2% to 7%). Possessing this variant increases the risk of pulmonary toxicity when exposed to thioureas, a widely used class of industrial compounds. FMO2 may also be involved in the metabolism of drugs that are used to treat diseases that are prevalent in Africa. RESULTS AND CONCLUSION: We conducted a survey of g.23238C>T variation across Africa that revealed that the distribution of this SNP is relatively homogeneous across sub-Saharan Africa, with approximately one third of individuals possessing at least one FMO2*1 allele, though in some populations the incidence of these individuals approached 50%. Thus many sub-Saharan Africans may be at substantially increased health risk when encountering thiourea-containing substrates of FMO2. Analysis of HapMap data with the Long-Range Haplotype test found no evidence for positive selection of either 23238C>T allele and maximum-likelihood coalescent analysis indicated that this mutation occurred some 500,000 years before present. This study demonstrates the value of performing genetic surveys in Africa, a continent in which human genetic diversity is thought to be greatest, but where studies of the distribution of this diversity are few.

Incorporation of genetic model parameters for cost-effective designs of genetic association studies using DNA pooling.

BACKGROUND: Studies of association methods using DNA pooling of single nucleotide polymorphisms (SNPs) have focused primarily on the effects of "machine-error", number of replicates, and the size of the pool. We use the non-centrality parameter (NCP) for the analysis of variance test to compute the approximate power for genetic association tests with DNA pooling data on cases and controls. We incorporate genetic model parameters into the computation of the NCP. Parameters involved in the power calculation are disease allele frequency, frequency of the marker SNP allele in coupling with the disease locus, disease prevalence, genotype relative risk, sample size, genetic model, number of pools, number of replicates of each pool, and the proportion of variance of the pooled frequency estimate due to machine variability. We compute power for different settings of number of replicates and total number of genotypings when the genetic model parameters are fixed. Several significance levels are considered, including stringent significance levels (due to the increasing popularity of 100 K and 500 K SNP "chip" data). We use a factorial design with two to four settings of each parameter and multiple regression analysis to assess which parameters most significantly affect power. RESULTS: The power can increase substantially as the genotyping number increases. For a fixed number of genotypings, the power is a function of the number of replicates of each pool such that there is a setting with maximum power. The four most significant parameters affecting power for association are: (1) genotype relative risk, (2) genetic model, (3) sample size, and (4) the interaction term between disease and SNP marker allele probabilities. CONCLUSION: For a fixed number of genotypings, there is an optimal number of replicates of each pool that increases as the number of genotypings increases. Power is not substantially reduced when the number of replicates is close to but not equal to the optimal setting.

Mixture modeling of microarray gene expression data.

About 28% of genes appear to have an expression pattern that follows a mixture distribution. We use first- and second-order partial correlation coefficients to identify trios and quartets of non-sex-linked genes that are highly associated and that are also mixtures. We identified 18 trio and 35 quartet mixtures and evaluated their mixture distribution concordance. Concordance was defined as the proportion of observations that simultaneously fall in the component with the higher mean or simultaneously in the component with the lower mean based on their Bayesian posterior probabilities. These trios and quartets have a concordance rate greater than 80%. There are 33 genes involved in these trios and quartets. A factor analysis with varimax rotation identifies three gene groups based on their factor loadings. One group of 18 genes has a concordance rate of 56.7%, another group of 8 genes has a concordance rate of 60.8%, and a third group of 7 genes has a concordance rate of 69.6%. Each of these rates is highly significant, suggesting that there may be strong biological underpinnings for the mixture mechanisms of these genes. Bayesian factor screening confirms this hypothesis by identifying six single-nucleotide polymorphisms that are significantly associated with the expression phenotypes of the five most concordant genes in the first group.

Summary of contributions to GAW Group 12: multivariate methods.

Here we summarize the contributions to Group 12 of Genetic Analysis Workshop (GAW) 14, held in Noordwijkerhout, The Netherlands. The theme of this group, multivariate methods, covered a broad range of statistical applications. Most of the contributors considered Problem 1 of the GAW. However, one paper considered the bivariate analysis of two binary phenotypes generated by the simulated data in Problem 2. Some contributors focused on statistical issues involved in considering multiple variables, and others on extensions to the variance-components methodology for analysis of quantitative traits. Applications to the Collaborative Study on the Genetics of Alcoholism data identified a single-nucleotide polymorphism (SNP) on chromosome 4 associated with the ttth1-ttth4 phenotypes, and replicated previous findings of linkage on chromosome 4 for alcohol consumption, using microsatellite and SNP data.