Workshop Report

Genetics in Medicine (2011) 13, 841–847; doi:10.1097/GIM.0b013e318217477f

Consanguineous marriages, pearls and perils: Geneva International Consanguinity Workshop Report

Hanan Hamamy1, Stylianos E Antonarakis1, Luigi Luca Cavalli-Sforza2, Samia Temtamy3, Giovanni Romeo4, Leo P Ten Kate5, Robin L Bennett6, Alison Shaw7, Andre Megarbane8, Cornelia van Duijn9, Heli Bathija10, Siv Fokstuen1, Eric Engel1, Joel Zlotogora11, Emmanouil Dermitzakis1, Armand Bottani1, Sophie Dahoun1, Michael A Morris12, Steve Arsenault13, Mona S Aglan3, Mubasshir Ajaz14, Ayad Alkalamchi15, Dhekra Alnaqeb16, Mohamed K Alwasiyah17, Nawfal Anwer18, Rawan Awwad19, Melissa Bonnefin20, Peter Corry21, Lorraine Gwanmesia1, Gulshan A Karbani22, Maryam Mostafavi1, Tommaso Pippucci23, Emmanuelle Ranza-Boscardin1, Bruno Reversade24, Saghira M Sharif25, Marieke E Teeuw26 and Alan H Bittles27

  1. 1Department of Genetic Medicine and Development, University of Geneva Medical School, and University Hospitals of Geneva, Geneva, Switzerland
  2. 2Stanford University Medical School, Center of Human Population Genetics, Institute of Molecular Genetics of the Italian National Research Council, University of Pavia, Milano, Italy
  3. 3Human Genetics and Genome Research Division, Clinical Genetics Department, National Research Centre, Cairo, Egypt
  4. 4University of Bologna Medical School, Italy
  5. 5VU University Medical Center, Amsterdam, The Netherlands
  6. 6Department of Medicine, University of Washington Medical Center, Medical Genetics, Seattle, Washington
  7. 7Ethox Centre, Department of Public Health, University of Oxford, United Kingdom, Oxford, United Kingdom
  8. 8Medical Genetics Unit and Laboratoire Associé INSERM UMR_S910, Saint Joseph University; Beirut, Lebanon
  9. 9Department of Epidemiology and Biostatistics, Erasmus University Medical School, Erasmusmc, Rotterdam, The Netherlands
  10. 10Department of Reproductive Health and Research, World Health Organization, Geneva, Switzerland
  11. 11Hebrew University Jerusalem, Department of Community Genetics, Public Health services, Ministry of Health, Israel
  12. 12Department of Genetic and Laboratory Medicine, Geneva University Hospital, Geneva, Switzerland
  13. 13Génome Québec and Ecogene-21 Biobank, Chicoutimi, Quebec, Canada
  14. 14Institute for Health Research, University of Bedfordshire, Bedfordshire, United Kingdom
  15. 15Mental Health Section, PHC Department/Ministry of Health, Baghdad, Iraq
  16. 16University Diabetes Center, King Saud University, Riyadh, Saudi Arabia
  17. 17Aziziah Maternity and Children Hospital, Ministry of Health, Jeddah, Saudi Arabia
  18. 18Department of Obstetrics and Gynecology, Medical City, Baghdad, Iraq
  19. 19Hadassah University Medical Center, Jerusalem, Israel
  20. 20King's College, London, University of Oxford, United Kingdom
  21. 21Child Development Centre, Bradford Teaching Hospitals NHS Foundation Trust, United Kingdom
  22. 22The Leeds Teaching Hospitals, NHS Trust, Yorkshire Regional Genetic Service, Department of Clinical Genetics, Leeds, United Kingdom
  23. 23Laboratorio di Genetica Medica, Dipartimento di Scienze Ginecologiche, Ostetriche Pediatriche-Università di Bologna, Policlinico S. Orsola-Malpighi, Bologna, Italy
  24. 24Laboratory of Human Embryology, Institute of Medical Biology, A*STAR, Singapore
  25. 25Leeds Teaching Hospitals, Department of Clinical Genetics, Chapel Allerton Hospital, Leeds, United Kingdom
  26. 26VU University Medical Center, Department of Clinical Genetics and EMGO Institute for Health and Care Research, Amsterdam, The Netherlands
  27. 27Centre for Comparative Genomics, Murdoch University, and Edith Cowan University, Perth, Western Australia, Australia

Correspondence: Hanan Hamamy, MD, Department of Genetic Medicine and Development, CMU 9180-Rue Michel-Servet 1, CH 1211 Genève 4, Switzerland. E-mail: hananhamamy@yahoo.com.

Received 6 January 2011; Accepted 15 February 2011; Published online 6 May 2011.

Disclosure: The authors declare no conflict of interest.

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Abstract

Approximately 1.1 billion people currently live in countries where consanguineous marriages are customary, and among them one in every three marriages is between cousins. Opinions diverge between those warning of the possible health risks to offspring and others who highlight the social benefits of consanguineous marriages. A consanguinity study group of international experts and counselors met at the Geneva International Consanguinity Workshop from May 3 2010, to May 7, 2010, to discuss the known and presumptive risks and benefits of close kin marriages and to identify important future areas for research on consanguinity. The group highlighted the importance of evidence-based counseling recommendations for consanguineous marriages and of undertaking both genomic and social research in defining the various influences and outcomes of consanguinity. Technological advances in rapid high-throughput genome sequencing and for the identification of copy number variants by comparative genomic hybridization offer a significant opportunity to identify genotype-phenotype correlations focusing on autozygosity, the hallmark of consanguinity. The ongoing strong preferential culture of close kin marriages in many societies, and among migrant communities in Western countries, merits an equivalently detailed assessment of the social and genetic benefits of consanguinity in future studies.

Keywords:

consanguinity; consanguineous marriage; inbreeding; endogamy; fertility; stillbirths; infant mortality; congenital disorders; genetic counseling

Healthcare providers and genetics specialists have usually judged the overall impact of consanguineous marriage as being negative when assessed in terms of increased genetic risks to the offspring, as opposed to the potential social and economic benefits. A study group of international experts and counselors met at the Geneva International Consanguinity Workshop from May 3, 2010, to May 7, 2010,1 to discuss the known and presumptive risks and benefits of close kin marriages and to identify important future areas for research on consanguinity.

It has recently been suggested that inbreeding depression, defined as the deleterious effects that result from matings between related individuals, could be associated with epigenetic mechanisms rather than DNA sequence alterations.2 Most studies have indicated that inbreeding depression in humans is moderate in effect and can conveniently be analyzed by studying the “genetic load,” i.e., the reduction in fitness due to deleterious genes maintained in the population by mutation in the face of elimination by natural selection.3 Recently, however, healthier viable offspring was produced by inbreeding a freshly generated knock-out mouse line for cytochrome P450 genes. This finding indicated a possible beneficial epigenetic role in inbreeding, described as “inbreeding de-repression.”4

Novel technologies and updated perceptions in developmental and functional genetics and genomics may be applied to investigate potential genetic advantages with inbreeding. Research into the risks and benefits of consanguinity is best undertaken through collaboration between countries with high consanguinity rates and those with appropriate scientific expertise, and the requisite technological and financial resources. Collaborations of this nature should lead to the identification and characterization of many genes responsible for human diseases, with direct benefits both to the populations investigated and to a better understanding of the genetic bases of human health and disease worldwide.5

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COMPARATIVE GLOBAL CONSANGUINITY RATES AND PREFERRED RELATIONSHIPS

As illustrated in Figure 1, consanguineous marriage is traditional and respected in most communities of North Africa, the Middle East and West Asia, a transverse belt that runs from Pakistan and Afghanistan in the east to Morocco in the west, and in South India, with intrafamilial unions collectively accounting for 20–50+% of all marriages.6,7 First cousin unions (F = 0.0625) are especially popular, comprising 20–30% of all marriages in some populations (Table 1), in particular the paternal parallel subtype in Arab societies (Fig. 2) (On average, first cousins share one of eight of their genes inherited from their common ancestors (grandparents), so their progeny is autozygous at 1 of 16 of all loci, which is expressed as an inbreeding coefficient (F) of 0.0625.6 The mean inbreeding coefficient “α= ΣFimi, where Fi is the inbreeding coefficient of a specific category of consanguineous marriage and mi is the proportion of this category in the population.3,7,9,10

Fig. 1.
Fig. 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Global total consanguinity rates.6

Full figure and legend (314K)

Fig. 2.
Fig. 2 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Categories of consanguineous marriages.

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The prevalence of consanguinity and rates of first cousin marriage can vary widely within and between populations and communities, depending on ethnicity, religion, culture, and geography. Consanguineous marriages are also practiced among emigrant communities from highly consanguineous countries and regions, such as Pakistan, Turkey, the Maghreb, and Lebanon, now resident in Europe, North America, and Australia. In recent years, however, these marriages have been subjected to substantial criticism in a number of Western countries.

In clinical genetics, a consanguineous marriage is generally defined as a union between two individuals related as second cousins or closer (F ≤ 0.0156)6,11 (Fig. 2), but in highly consanguineous populations, pedigrees with complex consanguinity loops are commonplace (Fig. 3), arising from close kin unions in preceding generations. Reports on consanguinity rates may sometimes include marriages between third cousins or more distantly related individuals (F ≤ 0.0039).12 Although this discrepancy affects the total consanguinity rate, because of the lower coefficients of inbreeding in more remote unions, it does not markedly alter the mean inbreeding coefficient (α).

Fig. 3.
Fig. 3 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Complex pedigree illustrating multiple consanguineous marriages.

Full figure and legend (90K)

Unions between individuals with at least one common ancestor, such as those commonly occurring in religious and social isolates, villages and small towns, and within tribes, are referred to as intracommunity or endogamous marriages. The custom of endogamous marriage among individuals belonging to the same clan or tribe often results in an unequal distribution of founder mutations across populations. Allelic heterogeneity for very rare autosomal recessive disorders also has been observed in an increasing number of highly consanguineous populations, with the coexistence of multiple mutations encoding specific inherited disorders in Middle Eastern Arab, Jewish, and Druze communities, findings that have been ascribed to random mutational events and/or selective heterozygote advantage.13,14

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CONSANGUINITY AND SOCIAL STRUCTURE

Sociocultural factors, such as the maintenance of family structure and property, ease of marital arrangements, better relationships with in-laws, and financial advantages relating to dowry, seem to be strong contributory factors in the preference for consanguineous unions. In addition, there is a general belief that marrying within the family reduces the possibilities of hidden uncertainties in health and financial issues.11 Contrary to common opinion, consanguinity is not confined to Muslim communities. Many other religious groups, including the Lebanese, Jordanian, and Palestinian Christian populations, also practice consanguineous marriage, although to a lesser extent than among coresident Muslims,10,15,16 whereas in the Hindu population of South India, more than 30% of marriages are consanguineous, with 20+% between uncles and their nieces (F = 0.125).17

Close kin marriage can be a strategy of conservation, with cousin marriage providing excellent opportunities for the transmission of cultural values and cultural continuity.18 For these reasons, consanguineous unions are generally thought to be more stable than marriages between nonrelatives, although the data so far available on marital discord and divorce are small in number. In most Arab societies, patrilateral parallel cousin marriages are regarded as important in uniting members of the same descent group and keeping the education of offspring within the family line. These considerations may be particularly significant under conditions of social change and political or socioeconomic insecurity.19 Thus, higher rates of close kin marriage have been observed among certain minority ethnic groups, especially during the initial phases of settlement of emigrant communities and refugees.20 Conversely, in South India and according to Confucian tradition in China, although marriage between a man and his mother's brother's daughter is permitted, patrilateral parallel cousin unions are viewed as incestuous.11

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HEALTH IMPACT OF CONSANGUINITY

Consanguinity does not seem to be associated with elevated rates of miscarriages, as a large majority of studies have failed to detect any significant increase in fetal loss rates among consanguineous couples.8 A meta-analysis of stillbirths showed a mean excess 1.5% deaths among first cousin progeny, although data from three communities resident in a single study site were identified as significant outliers that raised the overall mean value.30

In a meta-analysis of the fertility of first cousin and nonconsanguineous couples, first cousins had a higher mean number of live births in 33 of the 40 studies, which translated into a mean 0.08 additional births per family (r2 = 0.67, P < 10−9).30 However, multinational studies among first cousin offspring also indicated a mean 1.1% excess in infant deaths (r2 = 0.61, P < 10×5) compared with nonconsanguineous progeny,30 with an equivalent excess of 3.5% in overall prereproductive mortality (r2 = 0.70, P < 10−5).7 Currently, it is unclear whether the apparent greater fertility of first cousin couples represents compensation for their increased risk of postnatal losses or may primarily be due to their younger mean age at marriage, earlier first pregnancy, and longer reproductive span.8,11,29

The prevalence of congenital anomalies in the offspring of first cousin marriages has been estimated to be 1.7–2.8% higher than the background population risk, mostly attributable to autosomal recessive diseases.8,3133 An increased 2% risk that first cousin couples will bear a child with an autosomal recessive disorder indicates that approximately 8% of these couples have an increased risk of 25% or more, whereas 92% of first cousin couples will not be at increased risk of the birth of an affected child (If the additional risk is less or more than 2%, the 8 and 92 percentages will change accordingly.34 Rare and novel autosomal recessive disorders have been widely reported from communities with high consanguinity rates,3542 as the main impact of consanguinity is the increased expression of rare autosomal recessive genetic disorders.

The association of consanguinity with major congenital malformations, including nonsyndromic neural tube defects and cleft lip and/or palate remains controversial. However, after controlling for confounders, there was a significantly increased risk of specific congenital heart defects in first cousin offspring.43 This association could variously suggest a recessive mode of inheritance, some effect on noncoding regulatory DNA, or the contribution of an epigenetic mechanism to congenital heart defects. Nevertheless, in South India, where uncle-niece and first cousin marriages are strongly favored,16 a genome-wide linkage analysis using high-density oligonucleotide microarrays was unable to identify a single gene of major effect in a clinically heterogeneous sample of cases born to consanguineous parents.44

Most of the literature on the effects of parental consanguinity on Down syndrome has concluded that no such association exists. However, in some populations, an elevated frequency of Down syndrome has been reported, and, for example, in an Arab village in Israel, multigenerational cases of Down syndrome within a single endogamous kindred could not be explained by advanced maternal age alone.33

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QUANTITATIVE TRAITS AND COMPLEX DISORDERS: IS CONSANGUINITY A DETERMINANT?

Most quantitative traits, such as height, skin and eye color, intelligence, and blood pressure, fall under the umbrella of multifactorial inheritance, with both genetic and environmental factors contributing to the trait etiology in varying proportions. The association of parental consanguinity with such traits is vague, with few published reports that have consistently controlled for nongenetic variables.

Complex disorders such as hypertension, coronary artery disease, diabetes, schizophrenia, autism, and cancer are also etiologically heterogeneous, with multifactorial inheritance suspected in most families and individual cases. High susceptibility genes could play a significant role in the expression of a complex disease, and if such genes are rare and transmitted in an autosomal recessive manner, then consanguinity could be a determining factor.7 To date, little has been published on the effects of consanguinity on the complex late-onset disorders that account for most of the global public health burden.7 The association of consanguinity with complex disorders can be studied using different approaches. For example, epidemiological surveys could compare the frequency of a disorder in the progeny of first cousin parents with that of unrelated parents, whereas case-control studies could compare the rates of first cousins among affected individuals and controls.

Highly consanguineous populations provide a unique opportunity to detect recessively inherited genes for diseases manifesting in late life, such as a study identifying multiple loci for Alzheimer disease in an Israeli Arab community.45 Investigators share the difficulty of adequately defining controls, especially as most complex disorders are late onset in nature, and there also is the difficulty of controlling for community endogamy, with no guarantee that cases and controls belong to the same subpopulation. Perhaps for these reasons, association studies on consanguinity and breast cancer, and the frequency of BRCA 1 and BRCA2 in highly consanguineous populations, have so far produced contradictory opinions.46,47

Some studies have reported higher rates of specific complex disorders among consanguineous progeny, e.g., a small but significant increase in the rate of cousin marriages among the parents of Bedouin Arab schizophrenia patients in southern Israel.48 Similarly, in a religious isolate in The Netherlands, familial aggregation of several complex disorders, including ischemic stroke, was noted. Small effective population sizes and a high cumulative level of consanguinity make such populations valuable for locating and identifying novel genes, and incipient problems of ensuring rigorous matching of cases and controls are easier to control.49 However, in most populations, unambiguous evidence-based conclusions have been difficult to establish.

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PROSPECTS FOR GENETIC RESEARCH ON CONSANGUINITY

Discovery of the functional genomic elements that harbor pathogenic mutations is a major step toward a mechanistic understanding of the physiopathology of the phenotype and provides targets for therapeutic interventions. The technological advances in rapid high-throughput genome sequencing and for the identification of copy number variants by comparative genomic hybridization, therefore, offer unprecedented opportunities to identify a large number of additional links between genotypes and phenotypes in consanguineous families.

In the past, epidemiological studies based on consanguinity could approximately estimate the prevalence of autosomal recessive disorders in a community. Today, new approaches for estimating the frequency of autosomal recessive disorders can use molecular characterization of mutations in the affected offspring of consanguineous couples. The rationale of this new approach is based on a comparison of the frequency of identical or nonidentical mutations in children born to consanguineous parents. In the latter situation, as two mutated alleles are not identical by descent (IBD), they must have been inherited through two different ancestors of the consanguineous parents, or one is a de novo mutation.

A positive correlation has been postulated between the frequency of affected individuals in whom the alleles were not IBD and the frequency of pathologic alleles (q).50 The population prevalence of autosomal recessive diseases can be inferred using an equation that incorporates the frequencies of the mutant alleles and the coefficient of inbreeding (F) (unpublished data), with the results integrated into Locus-Specific Data Bases that have been rapidly increasing in number during the last decade.51 Novel research in consanguineous families should similarly focus on the proportion of DNA that is IBD in the parents of affected children compared with the parents of healthy children. Data of this nature potentially could provide more precise disease recurrence information to individual at-risk couples.34

Over the course of the past century, Mendelian and multifactorial traits have been perceived as existing at opposite ends of the genetic disease spectrum in humans, and the recent emphasis on genome-wide association studies for uncovering variants that underlie common diseases has potentially deepened this divide.52 It is envisaged that research in highly consanguineous populations could narrow this gap and that new genetic technologies could provide opportunities for comprehensive studies to define coding or regulatory factors implicated in human traits and disease in general, including complex diseases such as autism, diabetes, and cancer. Novel technologies and updated perceptions in developmental and functional genetics and genomics could also be applied to investigate the presence of any genetic advantages in consanguinity, which to date have relied heavily on computer modeling.

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CONCLUSIONS

A group of experts and international researchers meeting at the Geneva International Consanguinity Workshop from May 3, 2010, to May 7, 2010,1 discussed the known and presumptive risks and benefits of consanguineous marriages, and future prospects for research on consanguinity. The group highlighted the importance of evidence-based counseling recommendations for consanguineous marriages and for undertaking genomic and social research in defining the various influences and outcomes of consanguinity. There was a consensus that consanguineous marriages are associated with an increased risk of congenital malformations and autosomal recessive diseases, with some resultant increased postnatal mortality in the offspring of first cousin couples, but demographic and socioeconomic confounders need to be well controlled. No major adverse associations with reproductive parameters such as miscarriages and fertility have been documented. Associations with quantitative traits and complex adult-onset diseases are vague and inconsistent, suggesting the importance of implementing future research in this area. The group highlighted the importance of present-day robust molecular tools in conducting consanguinity research to better define genotype-phenotype correlations and assess the genetic risks and benefits of consanguinity. The presumptive social benefits of consanguineous marriages need to be confirmed by evidence-based research.

The efforts from the scientific community should be more geared to understanding the balance between the risks and benefits of consanguinity. This will help to define issues that are of greatest relevance to people in different lifestyle situations, whether there are situations which justify the discouragement, or possibly even the encouragement of consanguineous marriages and, if so, how best this advice might be given.

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References

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Acknowledgements

Contributors: H.H. drafted the report, A.H.B. drafted successive versions, and all other contributors revised the report and gave final approval for publication. All contributors actively participated in the workshop.