MOD Scores Research Articles

Shared and specific susceptibility loci for schizophrenia and bipolar disorder: a dense genome scan in Eastern Quebec families

The goal of this study was to identify susceptibility loci shared by schizophrenia (SZ) and bipolar disorder (BP), or specific to each. To this end, we performed a dense genome scan in a first sample of 21 multigenerational families of Eastern Quebec affected by SZ, BP or both (N=480 family members). This probably constitutes the first genome scan of SZ and BP that used the same ascertainment, statistical and molecular methods for the concurrent study of the two disorders. We genotyped 607 microsatellite markers of which 350 were spaced by 10 cM and 257 others were follow-up markers in positive regions at the 10 cM scan. Lander and Kruglyak thresholds were conservatively adjusted for multiple testings. We maximized the lod scores (mod score) over eight combinations (2 phenotype severity levels x 2 models of transmission x 2 analyses, affected/unaffected vs affected-only). We observed five genomewide significant linkages with mod score >4.0: three for BP (15q11.1, 16p12.3, 18q12-q21) and two for the shared phenotype, that is, the common locus (CL) phenotype (15q26,18q12-q21). Nine mod scores exceeded the suggestive threshold of 2.6: three for BP (3q21, 10p13, 12q23), three for SZ (6p22, 13q13, 18q21) and three for the CL phenotype (2q12.3, 13q14, 16p13). Mod scores >1.9 might represent confirmatory linkages of formerly reported genomewide significant findings such as our finding in 6p22.3 for SZ. Several regions appeared to be shared by SZ and BP. One linkage signal (15q26) appeared novel, whereas others overlapped formerly reported susceptibility regions. Despite the methodological limitations we raised, our data support the following trends: (i) results from several genome scans of SZ and BP in different populations tend to converge in specific genomic regions and (ii) some of these susceptibility regions may be shared by SZ and BP, whereas others may be specific to each. The present results support the relevance of investigating concurrently SZ and BP within the same study and have implications for the modelling of genetic effects.

Association of interleukin-10 promoter polymorphism with the incidence of multiple organ dysfunction following major trauma: results of a prospective pilot study.

A dysbalanced immune response is thought to account for a substantial part of the morbidity and mortality after severe trauma. The cytokine interleukin-10 (IL-10) suppresses the transcription of proinflammatory cytokines, mainly in macrophages and monocytes. The objectives of this prospective study in a level I trauma center in Germany were to examine the distribution of IL-10 promoter polymorphisms in a cohort of severely injured patients, to measure IL-10 cytokine levels and relate these to the genotype, and to identify associations of IL-10 polymorphisms with the incidence of severe multiple organ dysfunction syndrome (MODS). The genotypes of polymorphisms -592 and -1082 were determined by polymerase chain reaction (PCR) and restriction cleavage with Rsa 1 or Mnl I, respectively. We analyzed 119 severely injured trauma patients [mean Injury Severity Score (ISS) 38.0 +/- 13.2]. The frequency of the -1082A allele was 0.542, and that of the -592C allele was 0.807. IL-10 polymorphisms were not significantly associated with mean systemic IL-10 cytokine levels 6, 12, and 18 h after admission to the ICU. Carriers of the genotype -592AC had significantly higher overall MOD scores than non-AC carriers (P = 0.018; P(corr) = 0.036). The genotypes of the IL-10 SNP -1082 were not significantly associated with MOD scores. A multivariate Cox hazard regression analysis including important factors of the patients' anatomic and physiological trauma impact revealed only the shock index, the severity of the head injury, and the IL-10 -592 genotype AC as significant independent risk factors for the development of MODS. In this multivariate analysis, carriers of the genotype -592AC displayed a 3.3-fold increase in the relative risk of developing a MODS (P = 0.008, hazard ratio 3.29, 95% CI 1.36-7.97). Our data suggest a possible link between the AC genotype of the -592 single nucleotide polymorphism and significantly higher mean MOD scores. The AC genotype was associated in multivariate analysis with a higher relative risk of MODS in multiply injured patients. Further investigations in larger cohorts need to focus on the potential diagnostic and therapeutic options of this SNP.

A search for specific and common susceptibility loci for schizophrenia and bipolar disorder: a linkage study in 13 target chromosomes.

We report the first stage of a genome scan of schizophrenia (SZ) and bipolar disorder (BP) covering 18 candidate chromosomal areas. In addition to testing susceptibility loci that are specific to each disorder, we tested the hypothesis that some susceptibility loci might be common to both disorders. A total of 480 individuals from 21 multigenerational pedigrees of Eastern Québec were evaluated by means of a consensus best-estimate diagnosis made blind to diagnoses in relatives and were genotyped with 220 microsatellite markers. Two-point and multipoint model-based linkage analyses were performed and mod scores (Z, for max Z(max)) are reported. The strongest linkage signals were detected at D18S1145 (in 18q12; Z = 4.03) for BP, and at D6S334 (in 6p 22-24; Z(het) = 3.47; alpha = 0.66) for SZ. Three other chromosomal areas (3q, 10p, and 21q) yielded linkage signals. Chromosomes 3p, 4p, 5p, 5q, 6q, 8p, 9q, 11q, 11p, 12q, 13q, 18p and 22q showed no evidence of linkage. The 18q12 results met the Lander and Kruglyak (1995) criterion for a genome-wide significant linkage and suggested that this susceptibility region may be shared by SZ and BP. The 6p finding provided confirmatory evidence of linkage for SZ. Our results suggest that both specific and common susceptibility loci must be searched for SZ and BP.

Abstracts for the IXth World Congress of Psychiatric Genetics, Saint Louis, Missouri

Abstracts for the IXth World Congress of Psychiatric Genetics, Saint Louis, Missouri

Model-free linkage analysis: performance under real-world conditions.

The simulated data of the Genetic Analysis Workshop 12 problem set affords an ideal environment for testing real-world performance of model-free linkage analysis methods. To this end, we applied three different methods of model-free linkage analysis: mod scores [Hodge and Elston, Genet Epidemiol 11:329-42, 1994], maximized maximum lod score (MMLS) [Greenberg et al., Am J Hum Genet 63:870-9, 1998], and nonparametric linkage (NPL) scores [Whittemore and Halpern, Biometrics 50:118-27, 1994], as well as standard parametric linkage analysis to the detection of major gene 6 (MG6) using only the qualitative disease status data. Our results indicate that both mod scores and NPL scores perform well, even in the presence of an extremely complicated disease model. MMLS analysis did not perform well, except at the disease locus itself.

Linkage analysis of asthma and atopy including models with genomic imprinting.

Asthma and atopy are two closely related, common complex traits in which a number of genetic and environmental factors are suspected to play a role. We have performed parametric and nonparametric multi-marker linkage analysis for the Busselton data set, which is part of problem 1 of Genetic Analysis Workshop 12. In particular, we have focused on the dichotomous trait atopy, as well as on dichotomized versions of the quantitative traits RASTI and loge slope. The lod score analysis with adequate modeling of a parent-of-origin effect, by use of the program GENEHUNTER-IMPRINTING, was a special interest. The most prominent findings are a multipoint mod score of 3.12 at D13S153 for RASTI, and a multipoint mod score of 4.32 at the same locus for atopy, both with four-penetrance imprinting models that point to a gene subject to maternal imprinting. In addition, there are marked differences between imprinting and non-imprinting mod scores. These results corroborate earlier findings of linkage between atopy and D13S153, but add the aspect of paternal gene expression. Furthermore, suggestive evidence for linkage to atopy is found near D6S291, D7S530, and D14S74. The best-fitting models for chromosome 6 and 14 may suggest that genomic imprinting takes plae at these two loci as well.

Testing the utility of mod scores and sib‐pair analysis to detect presence of disease susceptibility loci

Testing the utility of mod scores and sib‐pair analysis to detect presence of disease susceptibility loci

Influence of multiple organ dysfunction syndrome on duration of critical illness and hospitalization.

Multiple organ dysfunction syndrome (MODS) is the leading cause of death in the general surgery intensive care unit (SICU). The development of MODS is a powerful predictor of prolonged SICU stay in survivors and nonsurvivors of critical illness, but its relation to less severe illness and briefer duration of care is unknown. To determine the relation between modest degrees of MODS and length of stay in the SICU and hospital and whether daily MOD score calculations can distinguish survivors from nonsurvivors before the SICU stay becomes prolonged. An SICU of a university tertiary care medical center. Prospective inception-cohort study. Illness severity data were collected in retrospect only for the calendar year 1991. Of 2646 consecutive patients studied, 115 stayed in the SICU more than 21 days. Acute Physiology and Chronic Health Evaluation (APACHE) II and III scores were calculated after 24 hours, with daily and cumulative MOD scores (0-4 points for 6 organs, 24 points maximum). Patients were followed up until hospital discharge or death. Data analysis was performed by unpaired 2-tailed t test, exact contingency analysis for multiple groups, univariate 1- or 2-way analysis of variance with repeated measures, or linear or polynomial regression tests as appropriate, alpha = .05. The mean (+/-SEM) age of the patients was 65 +/- 1 years; mean (+/-SEM) APACHE II score, 13.8 +/- 0.2; APACHE III score, 44.2 +/- 0.7; incidence of MODS, 1173 of 2646 patients, 44.3%; and hospital mortality rate, 9.2%. Cumulative MOD scores correlated closely with SICU length of stay in survivors, especially for SICU stays of less than 10 days (R2 = 0.99, P < .001). Similar correlations existed between the prevalence of MODS related to the increasing length of the SICU stay (R2 = 0.98, P < .001) and between the length of hospital stay and the cumulative MOD score (R2 = 0.79, P < .05). Daily MOD scores in patients whose SICU stay was more than 21 days distinguished survivors from nonsurvivors by day 2 of the SICU stay (P < .05) and thereafter. Modest degrees of MODS correlate closely with the duration of care in less severely ill patients. Early identification and daily quantitation of MODS may help identify patients at risk for prolonged illness and death. Prevention of outcomes that contribute to organ dysfunction is critical for reduction of length of stay and cost of care.

Determining linkage and mode of inheritance: mode scores and other methods.

The lod score method remains a popular approach for detecting linkage and estimating the recombination fraction theta between a marker locus and a trait locus. However, its implementation requires knowledge of all parameters of the genetic mechanism, including the number of loci involved and the genotype specific penetrance, which could depend on factors such as age. When some of the penetrance parameters phi are unknown, several methods are available, and have been reviewed by Hodge and Elston [(1994) Genet Epidemiol 11:329-342]. These include the "wrod score" (lod score maximized over theta under a wrong value of phi) and "mod score" (lod score maximized over both theta and phi) methods for inference on theta. It has further been proposed that the mod score also be used for estimating phi. In this paper, we review and assess the adequacy of these two methods for inferences on both phi and theta. In particular, all of the methods can be seen as variations on likelihood inference, using the information in the conditional likelihood for the marker data, given the trait data. The loss of efficiency of the mod is compared to that of the full likelihood, which utilizes all information available in the trait data. We also propose an alternative, based on the pseudo-likelihood, where phi is estimated via the trait information and plugged into the conditional likelihood. This method is compared to the mod score method, and the advantages and disadvantages of each are elucidated. In particular, it is seen that the pseudo-likelihood method can be more efficient than the mod score method if the ascertainment scheme can be modeled. As examples, both a random sample and a multiplex ascertainment scheme are considered. In addition, the pseudo-likelihood method leads to likelihood ratio tests for detecting linkage with a simple, known asymptotic reference distribution, a feature not shared by the mod score. Finally, we discuss the advantages of using the pseudo-likelihood method over the full likelihood method, both of which are valid when the ascertainment scheme is known.

Determining linkage and mode of inheritance: Mod scores and other methods

Determining linkage and mode of inheritance: Mod scores and other methods

Determining linkage and mode of inheritance: Mod scores and other methods

Determining linkage and mode of inheritance: Mod scores and other methods

TDT with covariates and genomic screens with mod scores: their behavior on simulated data.

We describe an extension to the TDT (transmission/disequilibrium test) which allows for more than two marker alleles and for covariates measured on the parent or offspring. We also describe a systematic genomic search where the mod score (maximized lod score) is computed for each marker under constraints on the population prevalence or penetrances of a single locus.