Population analysis and determination of the ethnic background are necessary in the study of multifactorial diseases: a study using the Dagestan population as a model

Psoriasis, a multifactorial disease with genetic predisposition, has been used as an example to study the role of the ethnic background in multifactorial diseases in the Dagestan population. The individual information card (IIC) is proposed as the main tool for correct collection and processing of information. The results of the study demonstrate that the Dagestan population is a convenient and adequate model population for studying multifactorial diseases, such as psoriasis, and may serve as an object for studying the role of heredity in the etiologies and pathogeneses of this and other multifactorial diseases.     

Interactive effect of two candidate genes in a disease: extension of the marker-association-segregation chi(2) method.

For elucidating the genetic component of multifactorial diseases, it is important to investigate the effect of several factors and the possible interaction between them. In particular, for many diseases it is interesting to study the interactive effect of two genes. In this context, the marker-association-segregation chi 2 method (MASC), initially proposed to detect the involvement of a candidate gene in multifactorial diseases, is developed here to investigate the involvement of two candidate genes and to model the joint effect of these two genes. In particular, it is possible to precisely determine whether the joint effect of both genes is multiplicative. This extension simultaneously uses information on two markers, one for each candidate gene, at both the population and the familial segregation level. We show here that there can be an important gai of power to detect the effect of a second gene in a disease when information is used simultaneously on two markers instead of studying each marker separately. This extension of MASC is then applied on a sample of insulin-dependent diabetes (IDD) families typed for the markers of two candidate regions: HLA and that of the insulin gene (INS). This analysis allows us to confirm the involvement of INS in IDD, and the best-fitting model is a multiplicative (noninteractive) effect of HLA and INS, with a biallelic locus for INS and a complementation model for HLA.     

Medico-genetic study of the population of Uzbekistan. I. Incidence and variety of hereditary pathology]

In district of the Samarkand province the screening for families burdened with multiple cases of non-infectious diseases was performed. The principles of the applied screening procedure are described in the present paper. In the course of clinical examination 98 families were detected, 55 of which included more than one person suffering presumably with Mendelian diseases and 43--with multifactorial disorders. Over 30 nosological forms were found, among which orthopaedic and neurological forms were the most frequent. As a rule, identical cases were detected in one or two families. The role of certain genetic processes in the distribution of hereditary diseases in the Uzbek population is discussed.     

The dagestan gene pool: The genetic structure of the nine largest ethnic groups: Analysis based on data on the AB0 and Rhesus blood groups

Detailed analysis of the population structure of Dagestan ethnic groups based on data on the AB0 and Rhesus blood groups has been carried out. A total of 32101 representatives of the nine largest ethnic groups of Dagestan (from 682 auls in 46 raions) have been examined. This allows a comprehensive genetic landscape of the Dagestan population to be drawn. Comparison of the ethnic groups studied with other Caucasian ethnic groups makes it possible to determine the position of the Dagestan gene pool in the total structure of the Caucasian gene pool.     

Blood polymorphism in the study of isolated communities

Isolated communities offer a unique opportunity for the study of biological and social consequences of consanguinity and migration. The studies of genetic polymorphisms have contributed greatly, not only to knowledge of the genetic constitution of a given individual and population, but also to clarify either relationship between structure and function of polymorphic traits or the susceptibility to multifactorial diseases, in which interaction between the gene and environment cannot be ignored. For over 25 years, we have investigated the effect of consanguinity and genetic polymorphisms in 9 isolated communities in Western Japan. We reported here different values of gene frequency for each polymorphic trait, compared with the neighboring communities and described how we applied these data to clarification of the genetic constitution of isolated communities as well as of genetic susceptibility to some diseases.     

Medical-genetic study of the population of the Lenkoran district of the Azerbaijani Republic

As a result of the genetic analysis of the population among the children’s population up to 14 years old of the Lenkoran district of the Azerbaijani Republic it was discovered that the phenotypic frequency of hereditary diseases and congenital malformation make up 0.274% according to the MLEC data and 5.12% according to self-made research. The high level of multifactorial and autosomo-recessive hereditary types indicates the high frequency of occurrence of marriages of genetic relatives in the district under study.     

Epidemiology of dysentery in Dagestan]

Analysis of material on bacterial dysentery and other acute intestinal infections morbidity in the Dagestan ASSR for a period of 15 years showed high morbidity level and its variations, with reduction and elevation in individual years, and the leading role played by Shigella flexneri among the causative agents of dysentery. The greatest incidence of dysentery was revealed among children aged under one year and between 1 and 2 years. A high bacterial dysentery incidence was recorded in Dagestan throughout the whole year. However analysis of the seasonal dysentery curve showed the beginning of elevation in July, reaching the maximum in August, and lasting four months with a decline beginning in October. The persisting activity of the water route of dysentery transmission in the Dagestan ASSR requires particular attention to the organization of good-quality water-supply to the population of the republic.     

Improving the prediction of complex diseases by testing for multiple disease-susceptibility genes

Studies have argued that genetic testing will provide limited information for predicting the probability of common diseases, because of the incomplete penetrance of genotypes and the low magnitude of associated risks for the general population. Such studies, however, have usually examined the effect of one gene at time. We argue that disease prediction for common multifactorial diseases is greatly improved by considering multiple predisposing genetic and environmental factors concurrently, provided that the model correctly reflects the underlying disease etiology. We show how likelihood ratios can be used to combine information from several genetic tests to compute the probability of developing a multifactorial disease. To show how concurrent use of multiple genetic tests improves the prediction of a multifactorial disease, we compute likelihood ratios by logistic regression with simulated case-control data for a hypothetical disease influenced by multiple genetic and environmental risk factors. As a practical example, we also apply this approach to venous thrombosis, a multifactorial disease influenced by multiple genetic and nongenetic risk factors. Under reasonable conditions, the concurrent use of multiple genetic tests markedly improves prediction of disease. For example, the concurrent use of a panel of three genetic tests (factor V Leiden, prothrombin variant G20210A, and protein C deficiency) increases the positive predictive value of testing for venous thrombosis at least eightfold. Multiplex genetic testing has the potential to improve the clinical validity of predictive testing for common multifactorial diseases.     

Identification of a novel gene and a common variant associated with uric acid nephrolithiasis in a Sardinian genetic isolate

Uric acid nephrolithiasis (UAN) is a common disease with an established genetic component that presents a complex mode of inheritance. While studying an ancient founder population in Talana, a village in Sardinia, we recently identified a susceptibility locus of approximately 2.5 cM for UAN on 10q21-q22 in a relatively small sample that was carefully selected through genealogical information. To refine the critical region and to identify the susceptibility gene, we extended our analysis to severely affected subjects from the same village. We confirm the involvement of this region in UAN through identical-by-descent sharing and autozygosity mapping, and we refine the critical region to an interval of approximately 67 kb associated with UAN by linkage-disequilibrium mapping. After inspecting the genomic sequences available in public databases, we determined that a novel gene overlaps this interval. This gene is divided into 15 exons, spanning a region of approximately 300 kb and generating at least four different proteins (407, 333, 462, and 216 amino acids). Interestingly, the last isoform was completely included in the 67-kb associated interval. Computer-assisted analysis of this isoform revealed at least one membrane-spanning domain and several N- and O-glycosylation consensus sites at N-termini, suggesting that it could be an integral membrane protein. Mutational analysis shows that a coding nucleotide variant (Ala62Thr), causing a missense in exon 12, is in strong association with UAN (P=.0051). Moreover, Ala62Thr modifies predicted protein secondary structure, suggesting that it may have a role in UAN etiology. The present study underscores the value of our small, genealogically well-characterized, isolated population as a model for the identification of susceptibility genes underlying complex diseases. Indeed, using a relatively small sample of affected and unaffected subjects, we identified a candidate gene for multifactorial UAN.     

Mapping genes of complex diseases in genetic isolates of Dagestan

Original results of the analysis of genetic linkage between some genomic markers and two complex clinical phenotypes, schizophrenia and mental retardation, in pedigrees from Dagestan genetic isolates are described. Interpopulation differences in the epidemiology of the complex phenotypes were studied and in their genetic linkage was demonstrated. These differences are evidently related to the genetic structure of the isolates determined by their genetic history. The MR epidemiological index characterizing the lifetime morbid risk of schizophrenia varies in the Dagestan isolates studied from 0 to 4.95%, which is almost five times higher than the average worldwide population rate, 1%. Comparative genetic mapping permitted determination of the most probable genetic linkages and associations of loci from chromosomal regions 17p11.1-12, 3q13.3, and a locus from 22q with schizophrenia and locus 12q23 with mental retardation. There is evidence that this approach is effective for detailed study of the relationship between the genetic (allele and locus) and clinical heterogeneity of complex diseases, which favors successful identification of the genes determining them. The study of linkage disequilibrium (LD) in genetic isolates of Daghestan populations (which have a common genetic background) may be an effective methodological approach for revealing the numerous contradictory results of mapping of the same genes of complex disease performed by different researchers in different regions of the world.     

Structure and Distribution of the Bird Population in Innermountain Dagestan

This paper analyses the results of bird counts carried out over the period of 1996–2017 in the Innermountain Province of Dagestan. The avian species composition, average population abundance, and ecological pattern of avifauna in a difficult-to-reach mountain area of the republic are described for the first time. Cluster analysis showed that population patterns of the considered sampling areas were not only similar, but also unique because of high heterogeneity of habitats and, consequently, faunal differences, which emerge in mountains under a lack of humidification. It is suggested that a specific pattern of the avifauna of Innermountain Dagestan is provided not only by resident communities of typical mountain birds, but also by adapted populations composed of migratory birds of valleys that nest in mountains.     

Variation of the parameters of natural reproduction and Crow’s indices in the ethnic groups of Dagestan

Using the 2002 All-Russian population census data, the parameters of differential fertility as a component of natural selection (Crow??s indices) have been calculated for women of seven age cohorts of the seven most numerous ethnic groups of the Republic of Dagestan. It has been shown that in the population of Dagestan in the second half of the 20th century the intensities of two types of selection tended to decrease, viz., intragroup selection relaxed in each ethnic group due to considerable reduction of interfamily variance in fertility and intergroup selection relaxed due to reduction of interethnic differences in fertility. A reduction of the average number of offspring (k) was observed in all ethnic groups, suggesting the spread of birth regulation practices (abortion and contraception). Nevertheless, all Muslim groups (aboriginal Dagestan ethnic groups and Azerbaijanis) are still characterized by an extended pattern of reproduction (2.7 < k < 3.3); in Russians k = 2.1. Interethnic differentials in natural reproduction rates, along with migration processes, account for the dynamics of the ethnic composition and gene-pool structure of the population of the Republic of Dagestan.     

Genomic study of the hereditary pathology and genetic diversity of the Siberian population

The review considers the results of genome research on the Russian program Human Genome carried out in the Institute of Medical Genetics (Tomsk) from 1990. The three major fields were molecular cytogenetics and chromosomal disorders, genomics of Mendelian and high-incidence diseases, and ethnogenomics of the North Asian population. Several human genes were cytogenetically mapped, and numerical and structural abnormalities associated with human diseases studied by fluorescence hybridization. Procedures of DNA diagnostics were developed for 15 hereditary diseases. New data were obtained on genetic heterogeneity of idiopathic hypertrophic cardiomyopathy. The genetic bases of multifactorial (atopic bronchial asthma) and infectious (tuberculosis) diseases were analyzed. The North Eurasian population (41 local populations of 21 ethnic groups) was tested for genetic diversity with numerous genetic markers, including Y-chromosomal haplotypes, autosomal microsatellites, and polymorphic Alu insertions.     

Modellvorstellungen zur Genetik multifaktorieller Krankheiten

In contrast to monogenic diseases, a straightforward genotype–phenotype relationship is unlikely for multifactorial diseases because of a number of genetic and nongenetic factors, including genetic heterogeneity, gene–gene and gene–environment interactions, and epigenetic mechanisms. As a consequence, the relative risk of particular genetic variants will generally be small, which implies that large sample sizes are required for their initial identification. No conclusions as to the frequency and diversity of the causative genetic variation can generally be drawn from the prevalence of a disease alone. Homogenization of the genetic background of the study population and the use of simple and clearly defined phenotypes together with “educated guesses” in candidate gene and gene–environment studies appear to be the most promising way to identify the genetic factors underlying multifactorial diseases. Replication of initial disease association findings, particularly for rare variants, should be carried out in populations that are genetically as similar as possible to the original population.     

Towards the genetic analysis of mulfactorial diseases: the estimation of allele frequency and epistasis

OBJECTIVES: The general aim of this paper is to reactivate the original intention behind the Elston-Stewart algorithm: i.e. physiological characterisation of the effects of individual loci underlying quantitative variation. The specific aim is the estimation of allele frequency and epistasis in multifactorial genetic diseases. METHODS: In a general genetic model, the probability of disease is a sigmoid function of the number of disease alleles summed over all loci. This model has just 4 parameters: the number of loci; the population frequency of disease alleles; a threshold expressed as a proportion of disease alleles; and the slope of the sigmoid curve. Assuming 10 loci, the remaining parameters can be estimated from empirical data: population frequency of the disease, monozygotic twin concordance rates, and disease frequency in sibs of affected probands. RESULTS: For 10 typical multifactorial diseases, the estimates of allele frequency are generally high, of the order of 20%, with strong epistatic interactions between loci. It follows that the frequencies of subphenotypes specific for a single disease locus will also be high, and only about two-fold greater in affected individuals than in normal controls. CONCLUSIONS: Because of allelic heterogeneity, purely genomic approaches are unlikely to succeed in unravelling the genetics of multifactorial diseases; this will rather require articulation with physiology and the identification of biologically meaningful subphenotypes.     

Multifactorial diseases: a nightmare for the geneticist

Common diseases are often familial, but they do not show in most families, a simple pattern of inheritance. In a few families these diseases may be caused by a mutation in a single gene. In most families these diseases are multifactorial, they result from a complex interaction between a genetic component which is often polygenic and many environmental factors. Two major, model free, methods are used to locate and identify susceptibility genes that predispose to multifactorial diseases. The first is a non parametric linkage analysis that relies on affected sib pairs, or an affected pedigree member, the second method is association studies which looks for increase frequency of particular alleles or genotypes in affected compared with unaffected individuals in the population. Most of the results have not been replicated, identifying susceptibility genes is proving much more difficult than most geneticists imagined 20 years ago. The main reason for this irreproducibility is genetic heterogeneity.     

Predisposition to multifactorial pathology in residents of the city in the zone around the "Maiak" atomic industry enterprise

According to present achievements in radiation and molecular genetics it is possible to expect that due to chronic radiation exposure the relative increasing of genetic risk in following generations will be observed. It will be due, in the first place, to increasing a percent of multifactorial diseases (MFD). Most of geneticists refer bronchial asthma (BA) to multifactorial diseases. Genetics and epidemiological analysis of liability to BA in population of Ozyorsk situated in the control area of "Mayak" Production Association (PA "Mayak") was accomplished. Population risk, as probability for an individual in population to develop BA up to the end of life is 2.69%. It's higher than in Moscow (2.03%) (p < 0.05). The excess is due to significantly higher values in females (2.96% against 1.93%). Population risk to fall ill of BA in females of Ozyorsk (2.96%) is significantly higher than in males (2.4%). Prevalence of BA in Ozyorsk (0.60%) is significantly higher than in Moscow (0.47%) due to higher values in females (0.65% against 0.47%). The total risk to fall ill of BA amongst relatives is 5.4% that is twice higher than the population risk. The heritability of BA is 0.71 (in Moscow-0.70).     

A genetic study of Hirschsprung disease

Hirschsprung disease, or congenital aganglionic megacolon, is commonly assumed to be a sex-modified multifactorial trait. To test this hypothesis, complex segregation analysis was performed on data on 487 probands and their families. Demographic information on probands and the recurrence risk to relatives of probands are presented. An increased sex ratio (3.9 male:female) and an elevated risk to sibs (4%), as compared with the population incidence (0.02%), are observed, with the sex ratio decreasing and the recurrence risk to sibs increasing as the aganglionosis becomes more extensive. Down syndrome was found at an increased frequency among affected individuals but not among their unaffected sibs, and the increase was not associated with maternal age. Complex segregation analysis was performed on these family data. The families were classified into separate categories by extent of aganglionosis. For cases with aganglionosis beyond the sigmoid colon, the mode of inheritance is compatible with a dominant gene with incomplete penetrance, while for cases with aganglionosis extending no farther than the sigmoid colon, the inheritance pattern is equally likely to be either multifactorial or due to a recessive gene with very low penetrance. A model of gene action with random effects during morphogenesis is compatible with our observations.     

Epidemiological studies on aging in France: from the PAQUID study to the Three-City study

Follow-up of cohorts recruited in general population with active screening and diagnosis of incident cases, is the most appropriate epidemiological design for studying incidence and risk factors of Alzheimer disease and other types of dementia. In France, people considered in the PAQUID study, then in the EVA study, have been the first cohorts on dementia. They have prepared the way for the Three-City (3C) study, conducted in Bordeaux, Dijon and Montpellier. About 9500 persons aged 65 years and over have been recruited in these three cities and will be followed-up during four years. The main objective of the 3C study is to investigate the relation between vascular risk and neurodegenerative diseases. The 3C study will provide essential data for defining strategies for dementia prevention. To measure the impact of the strategies on the incidence of dementia and the social burden of this disease will be an important public health objective in the near future.