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Study finds influence of parental relatedness on type 2 diabetes, other common diseases

Consanguinity is the social and cultural practice of marriage between two blood-related individuals who share a recent common ancestor, for example a grandparent or great-grandparent.

Study finds influence of parental relatedness on type 2 diabetes, other common diseases
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WASHINGTON: A recent study found that consanguinity, or marrying within a close family, may increase the risk of getting common diseases including type 2 diabetes and post-traumatic stress disorder (PTSD).

Researchers from the Wellcome Sanger Institute and their associates at Queen Mary University of London used a novel method that minimises confounding resulting from sociocultural factors to examine the relationship between autozygosity, a measure of genetic relatedness between an individual's parents, and the prevalence of common diseases. Their research focused on the Genes & Health cohort, which consists of British citizens with South Asian ancestry from the UK Biobank as well as individuals with European ancestry.

The Genes & Health Community Advisory Board worked with the researchers to produce a publicly accessible document aimed at the lay public, explaining the study's motivations, methodology, and findings1. The findings, published in Cell, help shed light on the complex interplay between genetics and health outcomes, especially among populations with higher rates of consanguinity.

Consanguinity is the social and cultural practice of marriage between two blood-related individuals who share a recent common ancestor, for example a grandparent or great-grandparent. This practice is observed across the world with varying prevalence. Over 10 percent of the global population consists of individuals who are the offspring of second cousins or closer2. In the UK, consanguinity is more common among some British South Asian communities. Consanguinity increases the fraction of an individual’s genome that is inherited identically from both parents, a phenomenon termed autozygosity.

While it is well established that consanguinity increases the risk of rare single-gene disorders by increasing the chance that an individual will inherit the same rare DNA change in a disease-causing “recessive" gene, its impact on common diseases remains understudied.

British Pakistanis and Bangladeshis have higher rates of several diseases than the UK average - for example a four-to-six-fold increased risk of developing type 2 diabetes compared to individuals of European ancestry3,4. However, these diseases involve a complex interplay of genetic and environmental factors, and, prior to this study, it was unknown whether consanguinity plays a role. In this new study, researchers from the Wellcome Sanger Institute and their collaborators set out to assess the impact of consanguinity on complex genetic diseases.

The teams analysed genomic data to describe different patterns of consanguinity in distinct populations, including 23,978 British individuals of Pakistani and Bangladeshi descent from the Genes & Health cohort, and 397,184 individuals of European or South Asian descent from the UK Biobank cohort. They found that ~33% of individuals in Genes & Health were offspring of second cousins or closer, versus 2% of individuals of European descent in UK Biobank. They then investigated the relationship between autozygosity and the prevalence of common diseases.

For this, they restricted their analysis to a set of ~5700 individuals in Genes & Health and UK Biobank with parents who were inferred to be first cousins based on the genetic data. Within this restricted ‘highly consanguineous’ group, the precise level of autozygosity is randomly determined, between 4 to 15 per cent, and the researchers showed that it is not correlated with sociocultural and environmental factors, such as religiosity, education or diet, which might themselves influence health traits.

This novel method helped ensure any observed links between autozygosity and diseases were biological in cause, rather than due to confounding.

Among the 61 complex genetic diseases examined in the Genes & Health and UK Biobank cohorts, researchers identified 12 diseases and disorders associated with increased autozygosity resulting from consanguinity. These included type 2 diabetes, asthma, and PTSD. The associations with type 2 diabetes and PTSD were then validated in a separate dataset from the consumer genetic company 23andMe Inc., using a between-sibling analysis technique5.

Analysis suggested that consanguinity may account for approximately 10 percent of type 2 diabetes cases among British Pakistanis and around 3 percent of cases among British Bangladeshis6. However, any health risks of consanguinity should be balanced with the positive social benefits of the practice as well as considered alongside other, more substantial modifiable risk factors, such as exercise, smoking and body mass index7.

This research reveals important insights into the factors influencing health outcomes and the associations between autozygosity and complex diseases within British Pakistani and Bangladeshi communities. It suggests that genetic studies of complex diseases should be broadened to pinpoint specific variants and genes with recessive effects.

Daniel Malawsky, first author of the study and PhD student at the Wellcome Sanger Institute, said: “While consanguinity has a smaller role in common diseases compared to other factors, it is still essential to understand its specific influence on health in these communities. Our new method exploring the natural variation in expected autozygosity amongst offspring of first cousins was a key breakthrough in helping us to test its impact. Some of our results suggested that cultural and environmental factors associated with consanguinity can sometimes exaggerate associations between autozygosity and health-related traits, or even mask truly causal associations. Our results suggest that some findings from previous studies linking autozygosity to complex traits in humans may have been misleading.”


ANI
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