A groundbreaking study has discovered unique genetic variants associated with multiple sclerosis that are specific to different ancestral backgrounds.
A groundbreaking study has discovered new genetic variants specific to different ancestral backgrounds that are associated with multiple sclerosis (MS). This offers fresh insights that could potentially change the way the disease is treated in various affected populations. The research, which was presented at ECTRIMS 2024, was conducted by the Alliance for Research in Hispanic MS (ARHMS) Consortium. It is the first extensive study to uncover genetic effects specific to ancestry that are linked to the risk of developing MS.
In a thorough analysis of over 7,000 individuals from self-reported Hispanic (n=4,313; 2,201 with multiple sclerosis, 2,112 controls) and African American (n=3,085; 1,584 with multiple sclerosis, 1,501 controls) backgrounds, researchers identified important genetic locations linked to the risk of multiple sclerosis (MS). These findings underscore the potential of genetic studies that consider ancestry to reveal previously unknown risk factors for MS and to enhance the accuracy of efforts to map the disease across different racial and ethnic groups.
A new genetic location has been discovered on chromosome 13q14.2, specifically within African genetic signatures. The variant, rs3803245, is situated in a chromosome region that is highly accessible to specific proteins in T-cells, indicating that this region may function as a regulatory site in T-cells. T-cells play a crucial role in the pathology of MS (multiple sclerosis).
The research has identified two distinct genetic variants associated with MS risk on chromosome 1p35.2. One variant is specific to Native American haplotypes, while the other is specific to European haplotypes. The Native American variant, rs145088108, significantly increases the risk of MS in Hispanics and African Americans (OR=2.05) compared to the European variant, rs10914539 (OR=1.37) based on data from a European cohort of 15,000 MS patients and 27,000 controls.
Dr. McCauley, a professor at the University of Miami Miller School of Medicine and the leader of the study, explains, “The variant found in Native American genetic signatures alters the structure of a protein, which might explain why it is more strongly associated with the risk of multiple sclerosis. In contrast, the variant found in European genetic signatures is located in a non-coding part of the gene, making it less clear how it contributes to the disease.”
In a cross-ethnic meta-analysis, the researchers successfully conducted a detailed mapping of seven known MS risk areas. Dr. McCauley added, “The genetic variations found in these areas could lead to the development of new, more targeted treatments for MS, some of which may be specific to certain populations. It is highly valuable to narrow down our focus to these regions, and with further research, there is potential to discover new targets for drug development in the future.”
“We anticipated finding some genetic diversity, but discovering African and Native American-specific alleles that affect the risk of multiple sclerosis is both exciting and encouraging. As our group of participants grows, we hope to find more ancestry-specific alleles that are important for understanding the different characteristics of the disease and addressing health differences in people with multiple sclerosis. We are very thankful to our study participants and their families for taking part in this important research, and we encourage more patients from underrepresented populations to join our efforts.”
UCLA Health researchers have published the largest-ever study of families with at least two children with autism, uncovering new risk genes and providing new insights into how genetics influence the development of autism.
The new study, published on July 28 in the Proceedings of the National Academy of Sciences, also provides genetic evidence that language delay and dysfunction should be reconsidered as a core component of autism.
The majority of genetic studies on autism have concentrated on families with a single affected child, often excluding families with multiple affected children. Consequently, very few studies have explored the impact of rare inherited genetic variations or their interaction with the collective effect of multiple common genetic variations that contribute to the risk of developing autism.
“Study design is critical, and not enough attention has been paid to studying families with more than one affected child,” said lead study author Dr. Daniel Geschwind, the Gordon and Virginia MacDonald Distinguished Professor of Human Genetics, Neurology, and Psychiatry at UCLA.
“Autism is highly heritable. It is estimated that at least 50% of the genetic risk is attributed to common genetic variations, while another 15-20% is due to spontaneous mutations or predictable inheritance patterns. The remaining genetic risk is still not completely understood.”
For this study, researchers conducted whole-genome sequencing on 4,551 individuals from 1,004 families, including 1,836 children with autism and 418 without.
The researchers found seven potential genes linked to autism: PLEKHA8, PRR25, FBXL13, VPS54, SLFN5, SNCAIP, and TGM1. This is notable because previous studies needed larger cohorts to find a similar number of new risk genes. Most of the new genes were supported by rare inherited DNA variations passed from parents to children with autism.
The researchers also looked into polygenic risk, which involves a combination of commonly found genetic variations that can increase the likelihood of developing autism. They discovered that children who inherit rare mutations from unaffected parents, combined with polygenic risk, are more likely to have autism. This helps to explain why parents who have a single rare mutation may not display signs of autism, even if their children do. It also supports the liability threshold model, a concept in behavioral genetics that suggests there is an additive effect of genes influencing the probability of developing a certain trait.
Children who experienced language delay were more likely to inherit a polygenic score linked to autism, compared to children without language delays. This association was specific to autism and was not observed for other traits such as educational attainment, schizophrenia, or bipolar disorder. This suggests a connection between the genetic predisposition for autism and language delay.
The most recent edition of the professional guidebook used by mental health providers to diagnose disorders, the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5), does not consider language delay a core symptom of autism. This is due to the variability in language ability among people with autism.
“This association of general risk for autism that was strongest in those with language delay suggests that language is actually a core component of autism. This finding needs to be replicated in larger cohorts, especially those recruited more recently under DSM-5,” Geschwind said.
The new study has found the genes that significantly increase a person’s risk of developing multiple sclerosis (MS) were introduced into north-western Europe around 5,000 years ago by sheep and cattle herders migrating from the east. CREDIT SayoStudio
Researchers have created the world’s largest ancient human gene bank by analysing the bones and teeth of almost 5,000 humans who lived across Western Europe and Asia up to 34,000 years ago.
By sequencing ancient human DNA and comparing it to modern-day samples, the international team of experts mapped the historical spread of genes – and diseases – over time as populations migrated.
The ‘astounding’ results have been revealed in four trailblazing research papers published today (10 January 2024) in the same issue of Nature and provide a new biological understanding of debilitating disorders.
The extraordinary study involved a large international team led by Professor Eske Willerslev at the Universities of Cambridge and Copenhagen, Professor Thomas Werge at the University of Copenhagen, and Professor Rasmus Nielsen at University of California, Berkeley and involved contributions from 175 researchers from around the globe.
The scientists found:
The startling origins of neurodegenerative diseases including multiple sclerosis
Why northern Europeans today are taller than people from southern Europe
How major migration around 5,000 years ago introduced risk genes into the population in north-western Europe – leaving a legacy of higher rates of MS today
Carrying the MS gene was an advantage at the time as it protected ancient farmers from catching infectious diseases from their sheep and cattle
Genes known to increase the risk of diseases such as Alzheimer’s and type 2 diabetes were traced back to hunter gatherers
Future analysis is hoped to reveal more about the genetic markers of autism, ADHD, schizophrenia, bipolar disorder, and depression
Northern Europe has the highest prevalence of multiple sclerosis in the world. A new study has found the genes that significantly increase a person’s risk of developing multiple sclerosis (MS) were introduced into north-western Europe around 5,000 years ago by sheep and cattle herders migrating from the east.
By analysing the DNA of ancient human bones and teeth, found at documented locations across Eurasia, researchers traced the geographical spread of MS from its origins on the Pontic Steppe (a region spanning parts of what are now Ukraine, South-West Russia and the West Kazakhstan Region).
They found that the genetic variants associated with a risk of developing MS ‘travelled’ with the Yamnaya people – livestock herders who migrated over the Pontic Steppe into North-Western Europe.
These genetic variants provided a survival advantage to the Yamnaya people, most likely by protecting them from catching infections from their sheep and cattle. But they also increased the risk of developing MS.
“It must have been a distinct advantage for the Yamnaya people to carry the MS risk genes, even after arriving in Europe, despite the fact that these genes undeniably increased their risk of developing MS,” said Professor Eske Willerslev, jointly at the Universities of Cambridge and Copenhagen and a Fellow of St John’s College, an expert in analysis of ancient DNA and Director of the project.
He added: “These results change our view of the causes of multiple sclerosis and have implications for the way it is treated.”
The age of specimens ranges from the Mesolithic and Neolithic through the Bronze Age, Iron Age and Viking period into the Middle Ages. The oldest genome in the data set is from an individual who lived approximately 34,000 years ago.
The findings provide an explanation for the ‘North-South Gradient’, in which there are around twice as many modern-day cases of MS in northern Europe than southern Europe, which has long been a mystery to researchers.
From a genetic perspective, the Yamnaya people are thought to be the ancestors of the present-day inhabitants of much of North-Western Europe. Their genetic influence on today’s population of southern Europe is much weaker.
Previous studies have identified 233 genetic variants that increase the risk of developing MS. These variants, also affected by environmental and lifestyle factors, increase disease risk by around 30 percent. The new research found that this modern-day genetic risk profile for MS is also present in bones and teeth that are thousands of years old.
“These results astounded us all. They provide a huge leap forward in our understanding of the evolution of MS and other autoimmune diseases. Showing how the lifestyles of our ancestors impacted modern disease risk just highlights how much we are the recipients of ancient immune systems in a modern world,” said Dr William Barrie, a postdoc in the University of Cambridge’s Department of Zoology and co-author of the paper.
Multiple sclerosis is a neurodegenerative disease in which the body’s immune system mistakenly attacks the ‘insulation’ surrounding the nerve fibres of the brain and spinal cord. This causes symptom flares known as relapses as well as longer-term degeneration, known as progression.
Professor Lars Fugger, a co-author of the MS study professor and consultant physician at John Radcliffe Hospital, University of Oxford, said: “This means we can now understand and seek to treat MS for what it actually is: the result of a genetic adaptation to certain environmental conditions that occurred back in our prehistory.”
Professor Astrid Iversen, another co-author based at the University of Oxford, said: “We now lead very different lives to those of our ancestors in terms of hygiene, diet, and medical treatment options and this combined with our evolutionary history means we may be more susceptible to certain diseases than our ancestors were, including autoimmune diseases such as MS.”
The new findings were made possible by the analysis of data held in a unique gene bank of ancient DNA, created by the researchers over the past five years with funding from the Lundbeck Foundation.
This is the first gene bank of its kind in the world and already it has enabled fascinating new insights in areas from ancient human migrations, to genetically-determined risk profiles for the development of brain disorders.
By analysing the bones and teeth of almost 5,000 ancient humans, held in museum collections across Europe and Western Asia, the researchers generated DNA profiles ranging across the Mesolithic and Neolithic through the Bronze Age, Iron Age and Viking period into the Middle Ages. They compared the ancient DNA data to modern DNA from 400,000 people living in Britain, held in the UK Biobank.
“Creating a gene bank of ancient DNA from Eurasia’s past human inhabitants was a colossal project, involving collaboration with museums across the region,” said Willerslev.
He added: “We’ve demonstrated that our gene bank works as a precision tool that can give us new insights into human diseases, when combined with analyses of present-day human DNA data and inputs from several other research fields. That in itself is amazing, and there’s no doubt it has many applications beyond MS research.”
The team now plans to investigate other neurological conditions including Parkinson’s and Alzheimer’s diseases, and psychiatric disorders including ADHD and schizophrenia.
They have received requests from disease researchers across the world for access to the ancient DNA profiles, and eventually aim to make the gene bank open access.
The research was funded by a €8M grant from the Lundbeck Foundation, and conducted at the Lundbeck Foundation Geogenetics Centre at the University of Copenhagen.
Jan Egebjerg, Director of Research at the Lundbeck Foundation, said: “The rationale for awarding such a large research grant to this project, as the Lundbeck Foundation did back in 2018, was that if it all worked out, it would represent a trail-blazing means of gaining a deeper understanding of how the genetic architecture underlying brain disorders evolved over time. And brain disorders are our specific focus area.”
‘Gene for chronic pain identified’ Do you have it?
A “gene responsible for chronic pain has been identified”, reports the BBC. It said that this could lead to drugs for treating long-lasting back pain.
This story is based on research carried out in mice. Researchers found that deleting a gene called HCN2 from the pain-sensing nerves in mice stopped them from having the chronic hypersensitivity to pain caused by nerve damage. However, their ability to sense short-term (acute) pain, for example from heat or pressure, was not affected.
This research has highlighted a potential role for HCN2 in one type of chronic pain, called neuropathic pain, produced by damage to nerves themselves. However, it’s important to note that this study was in mice and looked at the effect of removing the HCN2 gene rather than using chemicals to block its function. Therefore, it cannot tell us whether this strategy will be successful in treating human forms of chronic pain. This knowledge may help scientists to develop drugs to target this kind of pain in the future, but much more research will be needed to determine whether this will be the case.
Where did the story come from?
The study was carried out by researchers from the University of Cambridge and the University of Cadiz. Funding was provided by the UK Biotechnology and Biological Sciences Research Council, the European Union, Organon Inc. and a Cambridge Gates Foundation studentship. The study was published in the peer-reviewed journal Science .
The BBC provides a good description of this study, clearly stating that it was carried out in mice.
What kind of research was this?
This was animal research looking at whether an ion channel protein called HCN2 might play a role in the sensing of pain. Ion channels are protein “pores” in the cell membrane that control the flow of electrically charged atoms into or out of the cell. In nerves this flow of ions is essential for allowing them to transmit signals.
The researchers say that the frequency with which the nerves involved in sensing pain send signals to the brain (called their rate of firing) affects how intense a pain is felt to be. This rate could be influenced by ion channels, including the HCN ion channel family.
The HCN1 and HCN2 members of the HCN ion channel family are present at high levels in nerves involved in sensations such as pain and touch. Previous experiments have suggested that HCN1 does not play a large role in sensing pain, so the researchers wanted to investigate whether HCN2 might be important in sensing pain.
Animal and laboratory research is often the best way to investigate the role of individual proteins in biological processes, as researchers can remove individual genes and see what effect this has. This type of research could not be carried out in humans.
What did the research involve?
The researchers looked at the role of the HCN2 ion channel in mice by genetically engineering them to lack the gene that produces this protein in their pain-sensing nerves. They then looked at what effect this had on the ability of the pain-sensing nerves to send signals, and on how the mice sensed pain.
The researchers initially tried genetically engineering mice to lack the HCN2 gene throughout their bodies, but this led to the mice having serious movement problems and dying before they reached six weeks of age. They then decided to remove the HCN2 gene in the pain-sensing nerves only, so that these widespread adverse effects would not occur.
The researchers tested the mice’s responses to pain using standard tests. For example, they tested how quickly they withdrew their feet in response to touching a hot or cold surface or to the application of pressure (called painful ‘stimuli’). They also tested these responses after injecting the mice with chemicals that cause inflammation and make normal mice hypersensitive to these painful stimuli.
Finally, they looked at the effect of exposing these mice to long-lasting pain caused by damage to their nerves. This type of pain is called neuropathic pain. They used a standard way of replicating this type of pain, by placing pressure on the mice’s sciatic nerve. This usually makes mice more sensitive to painful stimuli.
What were the basic results?
The researchers found that mice that were genetically engineered to lack the gene for HCN2 in their pain-sensing nerves had disruptions to the normal electrical processes that led to firing of these nerves.
The HCN2-lacking mice did not show any change to their pain threshold on short-term exposure to heat or pressure. However, when injected with chemicals that cause inflammation and make normal mice hypersensitive to heat- and pressure-induced pain, the HCN2-lacking mice did not show hypersensitivity to heat-induced pain.
The HCN2-lacking mice also displayed the usual hypersensitivity to pressure-induced pain after the injection also seen in normal mice.
If the genetically engineered mice received a nerve injury, they did not show the increase in sensitivity to heat, cold or pressure that normal mice with this injury showed.
How did the researchers interpret the results?
The researchers concluded that the presence of HCN2 is necessary for the sensing of pain caused by nerve injury, called neuropathic pain. They say that HCN2 also appears to have a role in sensing inflammation-associated pain. They say that chemicals that can selectively block HCN2 may be useful as pain medication to block the effects of neuropathic and inflammatory pain.
Conclusion
This research has highlighted a potential role for HCN2 in one type of chronic pain, called neuropathic pain. This knowledge may help scientists to develop drugs to target this kind of pain.
Neuropathic pain is pain that arises from damage to or disorders of the nervous system. For example, the pain associated with spinal cord injury, shingles or from tumours pressing on nerves is neuropathic. This type of pain is reportedly difficult to treat with drugs.
Scientists will now be interested in finding chemicals that can block the action of HCN2, and testing the effect that such chemicals have on pain-sensing in animals. As removing HCN2 completely in mice had serious adverse effects, scientists would have to ensure that they could block the protein in such a way that reduced pain but did not have these adverse effects. Any chemicals that show promise and appear to be safe would then need to be tested in humans.
It is important to point out that this process of drug development takes a long time and is not always successful, with some chemicals that seem to have an effect in animals not working in humans.
Patau’s syndrome is a rare, serious genetic disorder caused by having an additional copy of chromosome 13 in some or all of the body’s cells. It’s also called trisomy 13.
Each cell normally contains 23 pairs of chromosomes, which carry the genes you inherit from your parents.
But a baby with Patau’s syndrome has three copies of chromosome 13, instead of two.
This severely disrupts normal development and, in many cases, results in miscarriage, stillbirth, or the baby dying shortly after birth.
Babies with Patau’s syndrome grow slowly in the womb and have a low birth weight, along with a number of other serious medical problems.
Patau’s syndrome affects about 1 in every 5,000 births. The risk of having a baby with the syndrome increases with the mother’s age.
More than 9 out of 10 children (over 90%) born with Patau’s syndrome die during the first year.
About 5-10% of babies with less severe forms of the syndrome, such as partial or mosaic trisomy 13, live for more than a year.
Symptoms and features
Babies with Patau’s syndrome can have a wide range of health problems.
Their growth in the womb is often restricted, resulting in a low birth weight, and 80% will be born with severe heart defects.
The brain often doesn’t divide into two halves. This is known as holoprosencephaly.
When this happens it can affect facial features and cause defects, such as:
Patau’s syndrome can also cause other problems, such as:
an abdominal wall defect where the abdomen doesn’t develop fully in the womb, resulting in the intestines being outside the body, covered only by a membrane – this is known as an exomphalos or omphalocoele
abnormal cysts in the kidneys
an abnormally small penis in boys
an enlarged clitoris in girls
There may also be abnormalities of the hands and feet, such as extra fingers or toes (polydactyly), and a rounded bottom to the feet, known as rocker-bottom feet.
Causes of Patau’s syndrome
Patau’s syndrome happens by chance and isn’t caused by anything the parents have done.
Most cases of the syndrome don’t run in families (they’re not inherited). They occur randomly during conception, when the sperm and egg combine and the foetus starts to develop.
An error occurs when the cells divide, resulting in an additional copy – or part of a copy – of chromosome 13, which severely affects the baby’s development in the womb.
In many cases, the baby dies before reaching full term (miscarriage) or is dead at birth (stillbirth).
In most cases of Patau’s syndrome (75-90%), a baby has a whole extra copy of chromosome number 13 in their body’s cells. This is sometimes known as trisomy 13 or simple trisomy 13.
In 5-10% of cases of Patau’s syndrome, genetic material is rearranged between chromosome 13 and another chromosome. This is called a chromosomal translocation.
Patau’s syndrome that arises because of this can be inherited. Genetic Alliance UK has more information about chromosome disorders.
In a further 5% of cases, only some cells have the extra copy of chromosome 13. This is known as trisomy 13 mosaicism. Occasionally, only part of one chromosome 13 is extra (partial trisomy 13).
The symptoms and features of both mosaicism and partial trisomy tend to be less severe than in simple trisomy 13, resulting in more babies living longer.
Screening for Patau’s syndrome
You’ll be offered a screening test for Patau’s syndrome – as well as Down’s syndrome (trisomy 21) and Edwards’ syndrome (trisomy 18) – from 10-14 weeks of pregnancy. The test assesses your chances of having a baby with these syndromes.
The screening test offered at 10-14 weeks of pregnancy is called the combined test because it involves a blood test and an ultrasound scan.
If the screening tests show that you have a higher risk of having a baby with Patau’s syndrome, you’ll be offered a diagnostic test to find out for certain whether your baby has the syndrome.
This test will check your baby’s chromosomes in a sample of cells taken from him or her.
Two techniques can be used to obtain the cell sample – amniocentesis or chorionic villus sampling (CVS). These are invasive tests to remove a sample of tissue or fluid so it can be tested for the presence of the extra copy of chromosome 13.
A newer test has recently been developed where a sample of blood from the mother is taken so that the baby’s DNA found within it can be tested. This is known as non-invasive prenatal testing, and is only available privately.
If you’re not able to have the combined screening test, you’ll be offered a scan that looks for physical abnormalities, including those found in Patau’s syndrome.
This is sometimes called the mid-pregnancy scan and is carried out when you’re between 18 and 21 weeks pregnant.
There’s no specific treatment for Patau’s syndrome. As a result of the severe health problems a newborn baby with the syndrome will have, doctors usually focus on minimising discomfort and ensuring the baby is able to feed.
For the small number of babies with Patau’s syndrome who survive beyond the first few days of life, their care will depend on their specific symptoms and needs.
If your baby is diagnosed with Patau’s syndrome, either before birth or shortly afterwards, you’ll be offered counselling and support.
Genetic testing for parents
Both parents will need to have their chromosomes analysed if their baby is affected by Patau’s syndrome caused by a chromosomal translocation.
Genetic testing is carried out to help parents plan for future pregnancies, rather than as part of the decision making process for the current pregnancy.
The test results will allow a more accurate assessment to be made of the likelihood of the syndrome affecting future pregnancies.
Other family members may also be affected and should be tested.
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