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Huntingtin gene in aging: beyond pathogenic associations

News
July 29, 2022
By
Olena Mokshyna, PhD.

How does common Huntingtin gene variations influence diverse traits in humans? The authors identified six unique gene variants connected to ten traits.

Huntingtin gene (HTT) is  well-known for its role in Huntington's disease – a neurodegenerative disorder that causes loss of movement control and cognition. This condition is caused by an expansion in one of the gene regions, primarily containing CAG (cytosine-adenine-guanine) nucleotide repeats. The number of CAG repeats can be used to predict Huntington onset, with earlier onset associated with a larger number of repeats. Individuals affected with the disease usually have an expansion of more than 35 CAG.

However, several recent studies found that human selection surprisingly favors longer CAG tracts in HTT. These studies proposed that the role of HTT spreads beyond its pathogenic influence, affecting neuronal function and multiple biological processes, such as autophagy and vesicular transport.

Slike and Wright explored the influence of common HTT variations on diverse traits in humans via large-scale genome-wide association studies (GWAS). The researchers analyzed mapping signals from GWAS, where HTT was identified as the most probable causing gene with high confidence.

GWAS data was obtained from the Open Targets Genetics database, a comprehensive data repository uniting both the UK Biobank and literature data. Extracted data contained information for more than 12 thousand independent significant loci (a specific position on a chromosome where a gene is located). 

After analyzing the data via a neural network model, the authors identified six unique gene variants connected to ten traits. These traits included cognitive and non-cognitive processes and longevity-related traits. Three groups of genetic variants were found to be responsible for these trait associations. Group one, responsible for approximately 70% of HTT associations, is connected to multiple longevity-related traits, including frailty index and parental lifespan. Frailty index calculates a proportion of deficits in individual over total number of age-related health issues while parental lifespan includes years of life of both parents. Both parameters are strongly linked to life expectancy. Increased expression of these variants was found to be lifespan-extending, with a calculated increase between 0.2 and 1 years. Groups two and three were primarily associated with independent educational attainment, personality, and psychiatric traits. 

This study presents the first systematic assessment of HTT variations' role in human disease and health. The authors were able to uncover multiple non-pathological associations of HTT at the human population level. Future functional studies must be performed to confirm these results. Understanding HTT beyond the narrow scope of pathology might help to develop novel approaches and interventions to support cognitive health and longevity.

Source Cell Death Discovery

Huntingtin gene (HTT) is  well-known for its role in Huntington's disease – a neurodegenerative disorder that causes loss of movement control and cognition. This condition is caused by an expansion in one of the gene regions, primarily containing CAG (cytosine-adenine-guanine) nucleotide repeats. The number of CAG repeats can be used to predict Huntington onset, with earlier onset associated with a larger number of repeats. Individuals affected with the disease usually have an expansion of more than 35 CAG.

However, several recent studies found that human selection surprisingly favors longer CAG tracts in HTT. These studies proposed that the role of HTT spreads beyond its pathogenic influence, affecting neuronal function and multiple biological processes, such as autophagy and vesicular transport.

Slike and Wright explored the influence of common HTT variations on diverse traits in humans via large-scale genome-wide association studies (GWAS). The researchers analyzed mapping signals from GWAS, where HTT was identified as the most probable causing gene with high confidence.

GWAS data was obtained from the Open Targets Genetics database, a comprehensive data repository uniting both the UK Biobank and literature data. Extracted data contained information for more than 12 thousand independent significant loci (a specific position on a chromosome where a gene is located). 

After analyzing the data via a neural network model, the authors identified six unique gene variants connected to ten traits. These traits included cognitive and non-cognitive processes and longevity-related traits. Three groups of genetic variants were found to be responsible for these trait associations. Group one, responsible for approximately 70% of HTT associations, is connected to multiple longevity-related traits, including frailty index and parental lifespan. Frailty index calculates a proportion of deficits in individual over total number of age-related health issues while parental lifespan includes years of life of both parents. Both parameters are strongly linked to life expectancy. Increased expression of these variants was found to be lifespan-extending, with a calculated increase between 0.2 and 1 years. Groups two and three were primarily associated with independent educational attainment, personality, and psychiatric traits. 

This study presents the first systematic assessment of HTT variations' role in human disease and health. The authors were able to uncover multiple non-pathological associations of HTT at the human population level. Future functional studies must be performed to confirm these results. Understanding HTT beyond the narrow scope of pathology might help to develop novel approaches and interventions to support cognitive health and longevity.

Source Cell Death Discovery

Article reviewed by
Dr. Ana Baroni MD. Ph.D.
SCIENTIFIC & MEDICAL ADVISOR
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Dr. Ana Baroni MD. Ph.D.

Scientific & Medical Advisor
Quality Garant

Ana has over 20 years of consultancy experience in longevity, regenerative and precision medicine. She has a multifaceted understanding of genomics, molecular biology, clinical biochemistry, nutrition, aging markers, hormones and physical training. This background allows her to bridge the gap between longevity basic sciences and evidence-based real interventions, putting them into the clinic, to enhance the healthy aging of people. She is co-founder of Origen.life, and Longevityzone. Board member at Breath of Health, BioOx and American Board of Clinical Nutrition. She is Director of International Medical Education of the American College of Integrative Medicine, Professor in IL3 Master of Longevity at Barcelona University and Professor of Nutrigenomics in Nutrition Grade in UNIR University.

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