Consanguinity

Advanced Topics Advanced Topics in Genomicsin Genomics

6-10-20116-10-2011

Prof. Moein Prof. Moein KanaanKanaan

Amer WazwazAmer Wazwaz

Consanguinity is a term, derived from two Latin words "con " means common, or of the same and "sanguineus " means blood Hence, referring to a relationship between two people who share a common ancestor or blood

In genetics, a consanguineous marriage means union between couples who are related as second cousins or closer Alwan A, Modell B

Endogamy is the marriage within a specific group or class with in the same population [isolated populations, small towns, villages or tribes]

IntroductionIntroductionLittle quantitative information on consanguinity is available from regions of high predisposition to consanguineous marriages

Different religious and cultural opinions and subsequently legislatives, most of them prohibit or even ban consanguineous marriages; especially first-cousin marriages

10.4% of the global population are related as second cousins or closer

Mortality in first-cousin progeny is ~3.5% higher than that in non-consanguineous offspring

Although the overall prevalence of consanguineous marriage seems to be declining, in some countries the present rates of consanguinity exceed those of the preceding generations like Qatar, Yemen, and UAE Tadmouri G.O et al

The Current Global Prevalence of Consanguineous Marriage

Global distribution of marriages between couples related as second cousins or closer

Consanguinity rates vary from one population to another depending on religion, culture and geography

Consanguinity Rates in Arab Populations

>1C Double first-

cousin marriage

1C First-cousin marriage

Source: Tadmouri G.O et al, Reproductive Health 2009.

Consanguinity Extent and Complexity

Influences and outcomes of consanguineous marriages

Contrasting biological and social outcomes of consanguineous marriage in

traditional rural and modern urban settings

Consanguineous marriages are generally thought to be more stable than marriages

between non-relatives

Societies with high consanguinity rates have to

understand and prevent the deleterious impact of consanguinity on health.

Guidelines for health care providers to assist them in

counseling for consanguinity

Population Stratification

Population stratification has critical importance in studying consanguinity-associated morbidity and mortality

Greater importance in larger populations with more diverse genetic origins

Population substructure often results in variant marker allele frequencies in different subpopulations

In most populations the clan or its hereditary equivalent may be the most logical unit for genetic screening

Influence of Consanguinity on Complex Diseases

Consanguinity expected to exert a greater influence on the complex diseases if rare autosomal recessive alleles were causally implicated, Whether in common disease/common variant or common disease /rare variant

While if the involved disease alleles are common in the gene pool, then intra-familial marriage would have a relatively lesser effect

Different impacts on adulthood complex diseases & congenital defects

For example: +ve for Schizophrenia and Alzheimer -ve for Breast Cancer and Hypertension

Dalmatian islands study indicated a positive association between inbreeding and a wide range of adulthood disorders

Ubiquitous involvement of rare autosomal recessive genes in adult-onset complex diseases. As an increasing in the genomewide heterozygosity after a decline in consanguineous marriage, lead to a widespread reduction in the burden of complex diseases

Pakistani community in the United Kingdom study examined the influence of first-cousin marriage on autosomal recessive single-gene disorders

A 7/1,000 increase in autosomal recessive disorders per 0.01 increase in the mean coefficient of inbreeding .

In the Pakistan national population, where 50% of marriages were between first cousins. Some 22/1,000 extra single-gene disorders would be expected

Comparative mortality in first cousin versus non-consanguineous progeny in 69

study populations

1C first cousin NC non-consanguineous

mean excess mortality at first-cousin level of 3.5%

Consanguinity and Consanguinity and Susceptibility to Infectious Susceptibility to Infectious

Diseases in HumansDiseases in Humans At least in Animal

Populations

Low genetic heterozygosity is a risk factor for infection by a diverse range of pathogens

In This Study

Microsatellite genome screen data

for tuberculosis, hepatitis and leprosy, used to test the

hypothesis that inbreeding depression increases risk of

infection

Studies link between genetic diversity and disease susceptibility are increasing

Two mechanisms may be responsible for maintenance of pathogens in a population

inbreeding depression and balancing selection It remains unclear if these animal studies have any relevance to human

Consanguinity has been implicated in susceptibility to a number of human diseases including heart disease, multiple sclerosis, depression and asthma

IntroductionIntroduction

In This First Study of its Kind in

HumansThey used microsatellite genome screen linkage

data for three infectious diseases in contrasting populations

tuberculosis in Gambia ,

hepatitis B both in Gambia and Italy and leprosy in India

To determine the extent of genomewide heterozygosity as an important predictor of susceptibility to some

diseases

Particularly in populations where inbreeding is common

Results

Strong association between consanguinity and human susceptibility to both TB and hepatitis B in West Africans

No significant association for hepatitis B in the Italians, probably due to the low levels of consanguinity

No significant association in the leprosy dataset in Indians, where the heterozygosity–heterozygosity correlations indicate similar levels of inbreeding in both cases and controls

Results

In two of three examples where a population has highlevels of consanguineous marriages, affected individuals reveal significant evidence of inbreeding compared with unaffected controls

Leprosy in India is an exception, as it thought to be strongly associated with two major effect loci /oligogenicity

Therefore, may be that persistent, strong inbreeding in the Indian populations has led to genetic purging

Correlations in heterozygosity among markers for affected and unaffected

individuals

A the entire datasetR affected family

%of consanguinity in each population is in brackets, * p>0.05, ** p>0.0009

stronger impact of consanguinity on

hepatitis than on TB

unaffected individuals yielded a higher

correlation than for affected individuals

Relationship between the strength of the heterozygosity and the proportion of inbred

individuals

second cousins

first cousins equal mixture

of the two

first-cousin marriages appear

necessary inorder to account

for the values observed in

Gambia

Consanguinity Management

Social awareness of consanguinity risks

Populations genetic screening

Counseling the youth

Warning who at risk

Conclusion