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PubMed1988

[Possibility of the current segregation analysis to discriminate between monogenic and multifactorial types of inheritance of traits. The effect of the structure of family data on model robustness and power of the analysis].

The influence of sampling designs for robustness of the autosomal major locus model and the multifactorial model as well as possibility of segregation analysis to discriminate these models was studied. Nuclear families and 3-generation pedigrees were considered. It was found that robustness of models increased, when the size of sibships in nuclear families grows and when configuration of pedigrees is complicated. The resolution power of the analysis is always increased with size elevation of sibships, the highest effect of the analysis being observed for sibships of the size 3 or 4. Consideration of new generations is only advisable, if attracting sibs of these generations, the resolution power being increased, provided that the parameters of models are of high value.

Genetics, Population↗
PubMed1981

Familial patterns and possible modes of inheritance of primary affective disorders.

A logistic model was used to analyze the pattern of affected relatives of probands with primary affective disorders (PAD). The sample consisted of 242 patients, diagnosed as either unipolar (UP, 107) or bipolar (BP, 135) and 430 control nonpsychiatric inpatients and all first degree relatives of both groups. Age correction was applied to both groups. The analysis showed a significant baseline increase in frequency of PAD among relatives of PAD probands with siblings more likely to be affected than parents. The difference in frequency of PAD according to sex of relative almost reached significance. Specific diagnosis (UP or BP) of proband did not significantly affect the probability of relatives becoming ill. Genetic models incorporating sex-specific thresholds were able to explain the data satisfactorily as resulting from either Single-Major-Locus inheritance or Multifactorial-Polygenic inheritance.

Bipolar Disorder↗
PubMed1991

Genetic studies of febrile convulsions: analysis of twin and family data.

Children with febrile convulsions (FC) including 46 twin pairs, 1913 families including 393 sibling pairs, and 42 three-generation FC kindreds have been studied. Twin studies: (1) The pairwise concordance rate for FC was 69% (18/26 pairs) in monozygotic (MZ) and 20% (4/20 pairs) in dizygotic (DZ) twins (P less than 0.01). (2) The intra-pair similarity of clinical symptoms in 18 concordant MZ twin pairs showed a positive significant correlation, particularly in 4 items--duration of seizure, exogenous factors, intelligence level, and background EEG abnormality. These correlations were greater than those in sibling pairs. (3) No evident cause for discordance was detected in 8 discordant MZ twin pairs, and many dissimilar symptoms were observed in 4 concordant DZ twin pairs. Sibship studies: A large positive correlation of some clinical symptoms was observed in sibling pairs concordant for FC: age at onset of FC, degree of fever, duration of seizure, exogenous factors, and background EEG abnormality (r = +0.2- +0.6). Family history analysis: Morbidity risk among near relatives (17% in parents, 23% in siblings) than in second- (6.1%) or third-degree relatives (4.6%). The difference was found between: sibling greater than parents, uncles greater than aunts, male cousins greater than female cousins. Segregation analysis showed maternal preponderance. In 42 three-generation kindreds the morbidity risk was higher in siblings (32%), uncles/aunts (14%), and cousins (6.4%) than in relatives of other probands. Characteristic findings in FC patients with family history: Characteristic findings in FC patients with an FC parent or sibling, compared with those with no family history, were early onset of FC, lower degree of fever, longer duration of seizure, many recurrences, FC recurrence after age 3, and background EEG abnormality. Similar findings were more markedly observed in 42 3-generation kindreds. Mode of inheritance: A multifactorial mode of inheritance for FC receives some support from this study, and the heritability was estimated as 75%.

Child, Preschool↗
PubMed1988

[The possibility of modern segregation analysis to discriminate monogenic and multifactorial types of the inheritance of traits. The reliability of models and the power of the analysis].

Using computer simulation of family data sets within segregation analysis limits the comparative research of the autosomal major locus model (MLM) and the multifactorial model (MFM) which described the basic types of inheritance of the alternative traits (affected--nonaffected) has been conducted. Robustness of models (statistical aspect) and the power of the analysis (its possibility to discriminate MLM and MFM) are tested. It is shown that permissible level of relative errors for estimated population's frequency is increased, when the values of parameters of models are increased (with decrease of sporadic cases' portion). The power of the analysis is the greatest in the field of greatest robustness of models: the higher the parameters of models, the portion of sporadic cases being low, the stronger the power of the analysis. MFM satisfactorily describes family distribution given by additive MLM. On the contrary, if the MLM corresponds to the multifactorial traits, this model is additive. It is shown that the possibility of the analysis to reject alternative model is decreased when determination of model grows down.

Genes↗
PubMed1981

Hereditary factors in the pathogenesis of affective illnesses.

The purpose of the study was verification of a genetic distinction between bipolar and unipolar affective illness and investigation of hypotheses concerning the mode of genetic transmission of both illnesses. The investigation demonstrated a difference between a group of 150 probands with bipolar affective illness and 50 probands with unipolar affective illness. A genetic-correlation analysis of both diseases showed that they are determined by different, partly correlated liabilities. Evaluation of the mode of inheritance suggests an multifactorial mode of inheritance of both affective illnesses: although genetic factors are of basic importance, continuously acting environmental factors also have a significant influence on the manifestation of the illness. The results suggest possible heterogeneity of both illnesses from the genetic standpoint.

Adult↗
PubMed2026

Polygenic risk score and its role in cancer susceptibility.

BACKGROUND: Polygenic risk score (PRS) has the ability to stratify inherited susceptibility to cancer and, as a complement to monogenic testing, can identify individuals at increased genetic risk even when no pathogenic variant is detected in high- or moderate-penetrance genes. It reflects the combined additive effects of a large number of low-penetrance variants across the genome, and represents a continuum of genetic susceptibility with an approximately normal distribution. Clinically relevant differences are typically observed in individuals in the highest and lowest percentiles of the PRS distribution, while relative risk gradients depend on the cancer type, the specific PRS model, and the reference population used. PRS is not a single test but rather a family of statistical models that differ in their design, predictive performance, and transferability across populations, underscoring the need for external validation and population-specific calibration of absolute risk. Broader implementation is thus still held back by differences between individual PRS models, limited transferability, and the lack of harmonized guidance on indication, reporting, and clinical decision-making. Consequently, clinical use in the European Union remains largely confined to pilot studies and local projects. Within these initiatives, PRS is most commonly applied in two main ways - either as a triage tool for intensified diagnostics or screening in higher-risk groups, or as a component of multifactorial absolute-risk models (e. g. BOADICEA/CanRisk) that integrate PRS with other risk factors such as pathogenic variants in moderate-penetrance genes (e. g. ATM or CHEK2), family history, or lifestyle factors. By refining absolute-risk estimates, PRS may shift individuals across clinical decision thresholds for more intensive surveillance and preventive strategies. AIM: This review summarizes the principles of PRS, the main sources of variability between models, and its potential applications in risk stratification and personalized cancer screening. It also addresses limitations in transferability, the need for calibration, and the currently limited evidence for improvements in hard clinical outcomes.

Humans↗
PubMed1977

[Genetic aspects of keratoconus (author's transl)].

The diverging views expressed in the literature on the inheritance of keratoconus gave us cause to examine the genetic relationships in 304 cases of keratoconus from our own clinic material. In the 22 cases (19 families) where two or more family members were affected, the genetic relationships generally indicated a multifactorial mode of inheritance, although isolated dominant or recessive variants could not be excluded. The assumption of a multifactorial inheritance is further supported by the occurrence of keratoconus in connection with various syndromes, as well as the fact that keratoconus does not only express itself in sharply defined stages, but also occurs in all possible degrees, from almost normal to the extreme.

Chromosome Aberrations↗
PubMed1979

A genetic study of febrile convulsions.

307 probands with febrile convulsions classed as the simple type (131 children) and the complicated type (176 children) were genetically analyzed. There was a tendency toward familial aggregation of febrile convulsions, and genetic involvement was suggested. The multifactorial mode of inheritance best agreed with the observations. (1) The ratio of incidence of febrile convulsions in siblings of probands in the present study (19.9%) to the incidence in the general population (2.9%), i.e., 6.85, was rather close to the expected ratio of 5.87 from the multifactorial inheritance system. (2) The incidence in siblings tended to be higher when either or both of their parents had a history of febrile convulsions. In 2-child families where the first child was affected, the incidence in the second child tended to increase in parallel with the increasing incidence in parents. (3) The incidence in siblings was higher if probands were males. (4) The heritability, when estimated by Falconer's procedure, was as high as 76%, showing that febrile convulsions are strongly genetically predisposed. These findings were more distinctly observed in the simple type than in the complicated type.

Adult↗
PubMed1986

The inheritance of pyloric stenosis explained by a multifactorial threshold model with sex dimorphism for liability.

The inheritance of pyloric stenosis is explained by a multifactorial threshold model with an underlying assumption that the liability for the disease is distributed in males and females showing a sex dimorphism. From the available data on familial occurrences of pyloric stenosis, it is shown, that an extra maternal effect is not required to explain the familial risk of pyloric stenosis, as opposed to the earlier literature. Explicit expressions for familial risks of a discontinuous trait exhibiting dimorphism of liability are presented, based on a model originally proposed by Rice et al [1981], which do not require the approximation of univariate normality of a conditional bivariate normal distribution.

Factor Analysis, Statistical↗
PubMed1981

Age-of-onset and genetic transmission in affective disorders.

Age-of-onset data were gathered on first-degree relatives of 252 probands with bipolar and unipolar affective disorders. Early onset probands (younger than 40 at onset) had more early onset relatives and a greater risk for affective disorder among their relatives than late onset probands (40 or older). This indicates that age-of-onset is a familial factor correlated with the liability to affective illness. Multiple threshold models of inheritance were applied to the data using age-of-onset as a liability-threshold determinant. The hypothesis of autosomal single-major locus was ruled out. Multifactorial-polygenic inheritance provided a better fit to the data. The data suggest that early and late onset affective disorders can be placed at different thresholds on a genetic environmental continuum and that the early onset form is more deviant genetically than the late onset type. The implications for genetic research in affective disorder are discussed.

Affective Disorders, Psychotic↗
PubMed1981

Application of the major gene index and offspring-between-parents function to dermatoglyphic fingertip variables.

Forty-eight digital dermatoglyphic variables in 192 nuclear families were analyzed to search for evidence of major gene effects, utilizing a pair of recently developed statistics called the major gene index (MGI) and offspring-between-parents (OBP) function. They operate on the principle that under a multifactorial blending inheritance scheme an offspring's phenotypic value approximates the midparental value, whereas under major gene inheritance, the child's value more closely resembles that of one of his parents. Both statistics yielded comparable results. All ridge-count variables showed no strong deviation from a multifactorial model. Pattern-type variables gave values suggesting the presence of major gene effects, but these results were probably the consequence of the variables' relatively discrete distributions, since a departure of a variable from a reasonably continuous phenotypic distribution was shown to interfere significantly with the interpretation of both statistics.

Chromosome Mapping↗
PubMed1982

Genetic models of schizophrenia.

Multiple threshold models of inheritance are applied to a large sample of Franz Kallmann's (1938) pedigree data on schizophrenia. Paranoid and nonparanoid subtypes are represented in the models at different thresholds on a continuum of genetic-environmental liability. Single major locus and multifactorial-polygenic inheritance are ruled out as modes of transmission. These findings suggest that the paranoid-non-paranoid dichotomy cannot be used as a genetic threshold determinant in the population studied.

Gene Frequency↗
PubMed1986

Cleft lip with or without cleft palate: reanalysis of a three-generation family study from England.

The study population consists of 424 three-generation families originally ascertained through nonsyndromic cleft lip with or without cleft palate (CL +/- P) surgical probands by Carter et al [J Med Genet 19:246-261, 1982] in London, England. Carter et al proposed that the multifactorial threshold model (MF/T) could explain the data. The goal of our study was to test that hypothesis, plus alternatives, rigorously. Two approaches were used: 1) Carter et al had proposed that these data were consistent with the predictions of the MF/T as presented by Carter [Br Med Bull 25:52-57, 1969]. However, we tested those predictions using standard chi 2 tests and found statistically significant departures from the predictions in these families. 2) Complex segregation analysis under the mixed model was performed. Again, the MF/T model could be rejected, as could a model of a major locus alone. The best-fitting model included both major locus and multifactorial components. When the data were analyzed in two parts based on the proband's phenotype (CL vs CL + P) there was some evidence of heterogeneity in that there was a significant proportion of sporadic cases in the families of CL probands but not in the families of CL + P probands. Our results provide no support for the MF/T model. The results from segregation analyses of CL +/- P in these families were most consistent with autosomal major gene inheritance plus multifactorial contributions.

Cleft Lip↗
PubMed1989

[Heredity and diseases of the organs of the urinary system: results and prospects of research].

The paper deals with current ideas of the role played by heredity in the development of diseases of the urinary system organs (USO). Hereditary nephropathies are divided into groups of disorders associated with chromosome aberrations (0.28 percent), monogen-inherited pathology (13 percent), multifactorial or polygen-inherited pathology (86.72 percent). Hereditary predisposition associated with antigenic determinants of the HIA system, immune, metabolic, histological defects and other factors are implicated in the development of multifactorial diseases. The pathways by which the disease predisposition is realized are nonuniform. There prospect well novel biotechnological approaches, virologic, pharmacogenetic studies aimed at understanding of the role of heredity in the development of USO disorders, at diagnosing borderline illnesses, and at preventing the disease manifestations.

Child↗
PubMed2025

Polygenic Prediction of Peripheral Artery Disease and Major Adverse Limb Events.

IMPORTANCE: Peripheral artery disease (PAD) is a heritable atherosclerotic condition associated with functional decline and high risk for limb loss. With growing knowledge of the genetic basis for PAD and related risk factors, there is potential opportunity to identify individuals at high risk using polygenic risk scores (PRSs). OBJECTIVE: To develop a novel integrated, multiancestry polygenic score for PAD (PRS-PAD) and evaluate its risk estimation for PAD and major adverse limb events in 3 populations. DESIGN, SETTING, AND PARTICIPANTS: This longitudinal cohort study was conducted among individuals with genotyping and electronic health record data in the UK Biobank (2006-2021), All of Us (AoU, 2018-2022), and the Mass General Brigham Biobank (MGBB, 2010-2023). Data were analyzed from July 2023 to February 2025. EXPOSURES: PRS-PAD, previously published PAD polygenic scores, and clinical risk factors. MAIN OUTCOMES AND MEASURES: The primary outcomes were PAD and major adverse limb events, defined as a surrogate of major amputation and acute limb ischemia. RESULTS: The study populations included 400&#x202f;533 individuals from the UK Biobank (median [IQR] age, 58.2 [45.0-71.4] years; 216&#x202f;215 female participants [53.9%]), 218&#x202f;500 from AoU (median [IQR] age, 53.6 [37.7-65.0] years; 132&#x202f;647 female participants [60.7%]), and 32&#x202f;982 from MGBB (median [IQR] age, 56.0 [32.0-80.0] years; 18&#x202f;277 female participants [55.4%]). In the UK Biobank validation cohort, PRS-PAD was associated with an odds ratio [OR] per SD increase of 1.63 (95% CI, 1.60-1.68; P&#x2009;<&#x2009;.001). After adjusting for clinical risk factors, the OR for the top 20% of PRS-PAD was 1.68 (95% CI, 1.62-1.74; P&#x2009;<&#x2009;.001) compared to the remainder of the population. Among PAD cases without a history of diabetes, smoking, or chronic kidney disease (n&#x2009;=&#x2009;3645), 1097 individuals (30.1%) had a high PRS-PAD (top 20%). In incident disease analysis, PRS-PAD improved discrimination (C statistic, 0.761), which was nearly equivalent to the performances of diabetes (C statistic, 0.760) and smoking (C statistic, 0.765). Among individuals with prevalent PAD, high PRS-PAD was associated with an increased risk of incident major adverse limb events in the UK Biobank (hazard ratio [HR], 1.75; 95% CI, 1.18-2.57; P&#x2009;=&#x2009;.005), MGBB (HR, 1.56; 95% CI, 1.06-2.30; P&#x2009;=&#x2009;.02), and AoU (HR, 1.57; 95% CI, 1.06-2.33; P&#x2009;=&#x2009;.03). CONCLUSIONS AND RELEVANCE: This cohort study develops a new PRS that stratifies risk of PAD and adverse limb outcomes. Incorporating polygenic risk into PAD care warrants further investigation to guide screening and tailor management to prevent major adverse limb events.

Humans↗