Use of isolated inbred human populations for identification of disease genes

doi:10.1016/S0168-9525(98)01556-X

Trends in Genetics

Volume 14, Issue 10, 1 October 1998, Pages 391-396

https://doi.org/10.1016/S0168-9525(98)01556-X Get rights and content

Abstract

The genetic mapping of disease loci involves the use of patient phenotype and genotype data in the search for genetic markers that segregate, or are associated with, a trait or disorder. Genetically isolated populations offer many advantages for such studies. The high degree of inbreeding and/or founder effects in some small population isolates result in an increased incidence of recessive disorders. Monogenic disorders are less likely to show non-allelic heterogeneity in isolated populations than in more diverse populations. The use of isolated populations also reduces the complexity of polygenic disorders by reducing the number of loci probably involved in the disorder. Finally, a variety of strategies can be used with particular efficacy for the mapping of disease genes in isolated populations.

Section snippets

Genetic complexity

Human diseases can be subdivided into etiologic categories ranging from disorders that are primarily genetic to those that are primarily environmental (Appendix A). In order to design studies aimed at identifying disease-causing genes, it is worthwhile to consider the types of genetic complexity that might be observed and how such complexity can be simplified. A common type of genetic complexity is the result of non-allelic genetic heterogeneity of monogenic disorders. This arises when

Consequences of genetic isolation

Groups that are isolated either physically or culturally are also frequently genetically isolated. Breeding within the group results in disease alleles and disease frequencies that differ from other groups. Inbreeding in our tribal ancestors was very high[22]; however, with the advent of agriculture, greater population density and wider mate selection, there was a world-wide relaxation of inbreeding, leaving this type of mate selection primarily to highly traditional communities. The frequency

Bedouin-Arabs of the Negev

One example of well-studied isolated populations are the Bedouin-Arabs of the Negev region of Israel (Fig. 1). These populations consist of about 90000 individuals, divided into numerous tribes, originating mostly from the nomadic Arabs of the Arabian peninsula desert, about 400 years ago. The Bedouin are Sunnite Muslims and, in spite of experiencing a strong westernization transition during the last decade, still maintain their tribal affiliations and cultural customs. The custom of

Use of novel mapping methods in isolated populations

The recent progress seen in the development of high-quality genetic markers and high-density human genetic maps has facilitated new strategies for mapping disease-causing and disease-susceptibility genes. These strategies, which include homozygosity mapping[40], DNA pooling38, 39and linkage disequilibrium16, 41, can be most successfully applied to disease mapping in genetically isolated populations, especially those in which consanguineous unions are common. Homozygosity mapping is based on the

Polygenic disorders

The use of isolated populations to reduce disease heterogeneity has also proved useful for more complex disorders, and it is this application of isolated populations that might prove most useful in future studies. Puffenberger et al.53, 54used members of an extended Mennonite kindred to map a locus for, and eventually identify, a gene causing Hirschsprung disease. This disorder results in the abnormal innervation of the distal large intestine, displays complex inheritance and is genetically

Limitations of inbred populations for disease-gene mapping

Although inbred populations are a powerful tool for disease-gene searches, their use also has its limitations. Some genetic markers that are highly informative in outbred populations are considerably less informative in an isolated population. This poses much less of a problem with the current availability of multiple, highly polymorphic, short tandem-repeat polymorphic markers. Differences in allele frequency between populations for given markers require that appropriate controls be identified

The use of genetic information

Apart from the contribution to general genetic knowledge, mapping of genes for rare diseases in isolated populations provides the opportunity to benefit the population being studied. Linkage data can be accurately applied for the purposes of early prenatal diagnosis and carrier detection. Clearly, such information needs to be used in a manner appropriate to the culture of the study population. The Negev Bedouin population provides an example whereby the results of molecular genetic research are

Acknowledgements

The authors acknowledge support from the National Institutes of Health. We appreciate the helpful suggestions of anonymous reviewers. We apologize that, owing to space limitations, many additional important articles could not be included in the review.

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Moreover, these same familial studies would enable more precise phenotypes to be described, thus leading to genotype-phenotype studies, especially in the case of rare variants (Guilmatre et al., 2009). In addition to epidemiological and clinical genetic studies, population genetic studies have shown that consanguinity reduced allelic heterogeneity and would potentially increase linkage disequilibrium, thus making it possible to detect associations between diseases and genetic markers (Sheffield et al., 1998). From a general standpoint, these results enforce the statement that the foundation to all association studies implicating complex diseases implicated a thorough understanding of the demographic and genetic structure of a population.
Consanguineous unions refer to marriages between related individuals who share a common ancestor. These unions are still commonplace in certain regions of the world such as the southern coast of the Mediterranean, throughout the Middle East and South-East Asia. According to available data, couples of second cousins or closer and their offspring currently represent 10.4% of the world's population, thus resulting in increased frequencies of autosomal recessive disorders. Furthermore, consanguinity may be implicated in the increased frequency of multifactorial pathologies such as mental disorders.
The few existing epidemiological studies in consanguineous and/or geographically isolated populations confirm that there is a significant association between consanguinity and mental disorders and a higher risk of schizophrenia or bipolar disorders among offspring from consanguineous couples.
There exists a strong and complex genetic component in the predisposition to psychotic disorders that has been confirmed in numerous studies. However, the genetic basis of these disorders remains poorly understood. GWAS studies (Genome Wide Association Studies) over the past 10 years have identified a few weak associations, thus refuting the “common diseases–common variants” hypothesis. A model implicating numerous rare variants has been supported by the recent discovery of CNVs (Copy Number Variants) and their statistically significant association with psychiatric disorders such as schizophrenia, bipolar disorders and autism.
The study of consanguineous families may contribute to identifying rare variants in homogenous populations who have conserved certain alleles. Major developments in molecular biology techniques would facilitate these studies as well as contributing to identifying major genes.
These results emphasize the need for genetic counseling in high-risk communities and the importance of implementing preventive actions and raising awareness concerning the risk of consanguineous unions.
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Consanguinity, schizophrenia and bipolar disorder
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La consanguinité est une relation entre deux personnes qui partagent un ancêtre commun. Elle est habituellement définie comme le résultat d’une reproduction sexuée entre deux individus apparentés. En d’autres termes, les mariages consanguins se réfèrent à des unions contractées entre des individus biologiquement liés. Ces unions sont encore fréquentes et constituent des pratiques très répandues dans certaines régions du monde. La région la plus concernée s’étend de la rive sud de la mer méditerranée à travers le Moyen-Orient, la Mésopotamie, le Golfe persique et l’Inde subcontinentale jusqu’au sud-est de l’Asie. Sur la base des données disponibles, il apparaît que les couples apparentés au second degré ou plus et leur progéniture représentent 10,4 % de la population mondiale actuelle. Leurs conséquences sur la fréquence des maladies à déterminisme génétique sont importantes et notamment en ce qui concerne les maladies autosomales récessives. Les études de jumeaux et d’adoption et les estimations du risque de survenue de troubles mentaux chez les apparentés de sujets atteints dans les études familiales ont confirmé l’existence d’une composante génétique dans la vulnérabilité à de nombreuses affections psychiatriques. Les techniques récentes d’examen du génome entier ou étude d’association pangénomique, en anglais genome-wide association study (GWAS), permettent d’identifier de plus en plus de gènes impliqués dans les troubles mentaux majeurs tels que la schizophrénie, l’autisme et le trouble bipolaire. Les études d’épidémiologie génétique auprès de populations consanguines et/ou constituant un isolat géographique mettent en évidence une augmentation des taux de mortalité et de morbidité infantiles, de la fréquence des maladies monogéniques récessives et une concentration accrue de maladies communes multifactorielles comme les troubles psychotiques. Elles confirmeraient l’existence d’un lien significatif entre consanguinité et troubles mentaux et l’augmentation du risque au sein de la descendance des couples consanguins. Ces études sur les liens entre consanguinité et troubles psychotiques sont peu nombreuses. Les rares données dont nous disposons semblent pourtant en faveur d’une augmentation de la fréquence de la schizophrénie et des troubles bipolaires dans la descendance de parents consanguins. La découverte récente des variants génétiques rares et leurs implications dans les troubles psychotiques constituent un argument en faveur de l’hypothèse « maladie commune-variants rares ». Dans ce cadre, l’étude de familles consanguines pourrait contribuer à tester les liens entre ces variants rares et quelques phénotypes et à établir des descriptions d’associations génotype/phénotype. Le développement de techniques nouvelles en génétique moléculaire devrait favoriser de telles études. L’ensemble de ces aspects mettent en évidence l’importance de l’étude des populations consanguines dans la compréhension du rôle des déterminants génétiques dans les pathologies psychiatriques et soulignent l’intérêt du conseil génétique pour ces communautés à hauts risques de troubles mentaux. Ils peuvent permettre également la mise en place de politiques de prévention et de sensibilisation sur les risques liés aux unions consanguines.
Consanguinity is a relationship between two people who share a common ancestor. It is usually defined as resulting from sexual reproduction between two related individuals. In other words, consanguineous marriages refer to unions which are contracted between two biologically linked individuals. These unions remain frequent and are widely practiced in certain areas of the globe. The most frequently concerned regions extend from the southern shore of the Mediterranean Sea, across the Middle East, Mesopotamia, the Persian Gulf and sub continental India extending into Southeast Asia. Based on available data, it appears that couples who are second-degree relations or closer and their offspring represent 10.4% of the world's current population. The consequences on the rates of genetically determined diseases are significant, especially in autosomal recessive diseases. Twin and adoption studies as well as risk estimations for the occurrence of mental disorders in families of patients who suffer from mental disorders have confirmed the existence of a genetic component in the vulnerability to numerous psychiatric diseases. Recent techniques examining the entire genome or pan-genomic association studies (Genome-Wide Association Studies or GWAS), have enabled us to identify increasing numbers of genes that are implicated in major mental disorders such as schizophrenia, autism and bipolar disorders. Epidemiological genetic studies in consanguineous populations and/or within geographic isolates have shown an increased rate in infant mortality and morbidity, monogenetic recessive diseases and common multifactorial diseases such as psychotic disorders. These confirm the existence of a significant link between consanguinity, mental disorders and increased risk within the offspring of consanguineous couples. Studies concerning the links between consanguinity and psychotic disorders are few. Rare available data seem to plead in favour of an increased frequency of schizophrenia and bipolar disorder in the offspring of consanguineous parents. The recent discovery of rare genetic variants and their implications in psychotic disorders represents an argument in favour of the “common disease-rare variants” hypothesis. Within this framework, the study of consanguineous families could contribute to testing the links between these rare variants and certain phenotypes and to establish descriptive genotype-phenotype associations. The development of new techniques in molecular genetics should facilitate such studies. All of these aspects show the importance of studying consanguineous populations in order to better understand the role of genetic determinants in psychiatric pathologies and to highlight the interest of genetic counselling in communities with increased risks of mental disorders. This may also enable governments to enact prevention policies and to launch awareness campaigns concerning the risks of consanguineous marriages.

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Trends in Genetics

Use of isolated inbred human populations for identification of disease genes

Abstract

Section snippets

Genetic complexity

Consequences of genetic isolation

Bedouin-Arabs of the Negev

Use of novel mapping methods in isolated populations

Polygenic disorders

Limitations of inbred populations for disease-gene mapping

The use of genetic information

Acknowledgements

Trends Genet.

Genomics

Genomics

Cell

Cell

Cell

Am. J. Hum. Genet.

Nature

Nat. Genet.

Nature

Nat. Genet.

Science

Science

Science

Nat. Genet.

Am. J. Hum. Genet.

Science

Am. J. Med. Genet.

Science

Am. J. Hum. Genet.

Science

Am. J. Hum. Genet.

Am. J. Hum. Genet.

Hum. Mol. Genet.

Science

Genetics

Lancet

Hum. Mol. Genet.

Am. J. Respir. Crit. Care Med.

Am. J. Hum. Genet.

Hum. Mol. Genet.

Hum. Mol. Genet.