22. March 2023

Beethoven’s genome offers clues to composer’s health and family history Beethoven’s genome offers clues to composer’s health and family history

International team of scientists deciphers renowned composer’s genome from locks of hair

Ludwig van Beethoven’s genome has been sequenced for the first time by an international team of scientists with the participation of the University of Bonn using five genetically matching locks of the well-known composer’s hair. 

Portrait of Beethoven
Portrait of Beethoven - by Joseph Karl Stieler, 1820. © Foto: Beethoven-Haus Bonn
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The research, led by the University of Cambridge, the Beethoven Center San Jose and American Beethoven Society, KU Leuven, FamilyTreeDNA, the University Hospital Bonn and the University of Bonn, the Beethoven-Haus, Bonn, and the Max Planck Institute for Evolutionary Anthropology, uncovers important information about the composer’s health and poses new questions about his recent ancestry and cause of death.

In 1802, Beethoven asked his doctor to describe his illness and to make this record public. The great man’s health and cause of death have been debated ever since, but without the benefit of genetic research.

Research published in Current Biology shows that DNA from five locks of hair – all dating from the last seven years of Beethoven’s life – originate from a single individual matching the composer’s documented ancestry. By combining genetic data with closely examined provenance histories, researchers conclude these five locks are “almost certainly authentic”.

The study’s primary aim is to shed light on Beethoven’s health problems, which famously include progressive hearing loss, beginning in his mid- to late-20s and eventually leading to him being functionally deaf by 1818. The team also investigated possible genetic causes of Beethoven’s chronic gastrointestinal complaints, and a severe liver disease that culminated in his death in 1827.

Beginning in his Bonn years, the composer suffered from “wretched” gastrointestinal problems, which continued and worsened in Vienna. In the summer of 1821, Beethoven had the first of at least two attacks of jaundice, a symptom of liver disease. Cirrhosis has long been viewed as the most likely cause of his death at age 56.

Genetic clues to Beethoven’s health

The team of scientists were unable to find a definitive cause for Beethoven’s deafness or gastrointestinal problems. However, they did discover a number of significant genetic risk factors for liver disease. They also found evidence of an infection with hepatitis B virus in at latest the months before the composer’s final illness.

Lead author, Tristan Begg, from the University of Cambridge, said: “We can surmise from Beethoven’s ‘conversation books’, which he used during the last decade of his life, that his alcohol consumption was very regular, although it is difficult to estimate the volumes being consumed. While most of his contemporaries claim his consumption was moderate by early 19th century Viennese standards, there is not complete agreement among these sources, and this still likely amounted to quantities of alcohol known today to be harmful to the liver. If his alcohol consumption was sufficiently heavy over a long enough period of time, the interaction with his genetic risk factors presents one possible explanation for his cirrhosis.”

The research team also suggests that Beethoven’s hepatitis B infection might have driven the composer’s severe liver disease, exacerbated by his alcohol intake and genetic risk. However, scientists caution that the nature and timing of this infection – which would have greatly influenced its relationship with Beethoven’s liver disease – could not currently be determined, and similarly caution that the true extent of his alcohol consumption remains unknown.

Beethoven’s hearing loss has been linked to several potential causes, among them diseases with various degrees of genetic contributions. Investigation of the authenticated hair samples did not reveal a simple genetic origin of the hearing loss. Dr. Axel Schmidt at the Institute of Human Genetics at the University Hospital of Bonn, said: “Although a clear genetic underpinning for Beethoven’s hearing loss could not be identified, the scientists caution that such a scenario cannot be strictly ruled out. Reference data, which are mandatory to interpret individual genomes, are steadily improving. It is therefore possible that Beethoven’s genome will reveal hints for the cause of his hearing loss in the future.”

It proved impossible to find a genetic explanation for Beethoven’s gastrointestinal complaints, but the researchers argue that coeliac disease and lactose intolerance are highly unlikely based on the genomic data. Beethoven was also found to have a certain degree of genetic protection against risk of irritable bowel syndrome (IBS), often suspected as a cause, rendering this a less likely explanation.

“We cannot say definitely what killed Beethoven, but we can now at least confirm the presence of significant heritable risk, and an infection with hepatitis B virus,” said Johannes Krause, from the Max Planck Institute of Evolutionary Anthropology. “We can also eliminate several other less plausible genetic causes.”

“Taken in view of the known medical history, it is highly likely that it was some combination of these three factors, including his alcohol consumption, acting in concert, but future research will have to clarify the extent to which each factor was involved,” Tristan Begg adds.

Authenticating Beethoven’s hair

In total, the team conducted authentication tests on eight hair samples acquired from public and private collections in the UK, continental Europe and the US. In doing so, the researchers discovered that at least two of the locks did not originate from Beethoven, including a famous lock once believed to have been cut from the recently deceased composer’s head by the 15-year-old musician Ferdinand Hiller.

Previous analyses of the ‘Hiller lock’ supported the suggestion that Beethoven had lead poisoning, a possible factor in his health complaints, including his hearing loss. William Meredith, who was part of a team involved in earlier scientific analyses of Beethoven’s remains and initiated the present study with Tristan Begg, said: “Since we now know that the ‘Hiller lock’ came from a woman and not Beethoven, none of the earlier analyses based solely on that lock apply to Beethoven. Future studies to test for lead, opiates, and mercury must be based on authenticated samples.”

The five samples identified as being authentic and from the same person belong to the Ira F. Brilliant Center for Beethoven Studies in San Jose, California; to a private collector, American Beethoven Society member Kevin Brown, and to the Beethoven-Haus in Bonn. Beethoven hand-delivered one of the locks (now in Brown’s collection) to the pianist Anton Halm in April 1826 telling him “Das sind meine Haare!” (“That is my hair!”). Beethoven’s whole genome was sequenced from another of Brown’s samples, the ‘Stumpff Lock’, which emerged as the best-preserved sample. The team found the strongest connection between the DNA extracted from the Stumpff lock of Beethoven's hair and people living in present day North Rhine-Westphalia, consistent with Beethoven's known German ancestry.

A family mystery

The team analysed the genetics of living relatives in Belgium but could not find matches among either of them. Some of them share a paternal ancestor with Beethoven in the late 1500s and early 1600s based on genealogical studies, but they did not match the Y-Chromosome found in the authentic hair samples. The team concluded that this was likely to be the result of at least one “extra-pair paternity event” – a child resulting from an extramarital relationship – in Beethoven’s direct paternal line. Genetic genealogist Maarten Larmuseau from the KU Leuven said: “Through the combination of DNA data and archival documents, we were able to observe a discrepancy between Ludwig van Beethoven’s legal and biological genealogy.”

The study suggests that this event occurred in the direct paternal line between the conception of Hendrik van Beethoven in Kampenhout, Belgium in 1572, and the conception of Ludwig van Beethoven seven generations later in 1770, in Bonn, Germany. Although a doubt had earlier been raised concerning the paternity of Beethoven’s father owing to the absence of a baptismal record, the researchers could not determine the generation during which this event took place.

Tristan Begg said: “We hope that by making Beethoven’s genome publicly available for researchers, and perhaps adding further authenticated locks to the initial chronological series, remaining questions about his health and genealogy can someday be answered."

“A clear genetic predisposition to liver cirrhosis”

State-of-the-art human genetic methods provide a clearer picture of Beethoven’s death

Prof. Dr. Markus Nöthen, Head of the Institute of Human Genetics and member of the Transdisciplinary Research Area Life & Health as well as the Cluster of Excellence ImmunoSensation2, was instrumental in interpreting the genome data of Ludwig van Beethoven. In an interview, he provides information on the findings of the current study.

How did the idea of sequencing Ludwig van Beethoven’s genome come about?
As early as 1999, an attempt was made to study a small part of the musician’s DNA, namely mitochondrial DNA. However, this did not work. Starting in 2014, plans were made to start a new attempt with the help of the much better and more modern method of “next-generation sequencing” and then also to take a look at Beethoven’s entire genome. The study was initiated by the American Beethoven Society, by Johannes Krause, then still at the University of Tübingen and since 2020 director at the Max Planck Institute for Evolutionary Anthropology in Leipzig, and by Tristan Begg, a masters student in Tübingen. Genetic matches were demonstrated between samples from five locks of Beethoven’s hair. The samples are therefore considered authentic. These were the basis for the new investigation.

How did the Institute of Human Genetics get involved in this project?
We are responsible for the medical interpretation of the genomic data. We were brought in when the extraction of the DNA from the locks of hair and the subsequent sequencing had been done and the DNA sequence data had to be interpreted in the next step. Our Bonn-based institute is known for focusing its research on the entire spectrum of genetic factors, from rare mutations with large effects that cause classic hereditary diseases to common mutations with smaller effects that determine the risk for common diseases.

Beethoven died in 1827. Hair from several curls of the musician was taken as a sample. What are the challenges of studying DNA that is nearly 200 years old?
The investigation was carried out with the help of archaeogenetic methods by Tristan Begg, now a doctoral student in the working group of Johannes Krause. The researchers extracted the DNA from the clipped hair of Ludwig van Beethoven. Because of its age, it is very degenerate DNA, broken into many short sections. Another challenge is that there is very little genetic material in hair compared to hair roots. However, Johannes Krause’s research group managed to reconstruct the genome from it to a large extent. This is done by sequencing the existing short sections of DNA using the latest, very sensitive methods and assembling the short sequences into larger genome sequences using computer algorithms, just like a jigsaw puzzle.

What did the Institute of Human Genetics contribute to the international study?
With my collaborators Axel Schmidt and Carlo Maj, who now works at the Marburg Institute of Human Genetics, I was responsible for the medical interpretation of the data. The challenge was to look for genetic causes in the genomic data based on the complexes of disease symptoms that have historically been passed down for Beethoven. We were able to enlist Christian Strassburg, Director of General Internal Medicine at the University Hospital Bonn, as a specialist in liver disease. Medical interpretations of genomic data are very complex and therefore require the skills of different disciplines.

What came out of these investigations in Bonn?
Three major symptom complexes have been passed down in Beethoven’s case, with progressive hearing loss probably being the best known. With regard to Beethoven’s hearing impairment, we found no evidence of the presence of classical, hereditary hearing loss. This did not surprise us either, because his hearing impairment did not appear until early adulthood. However, most inherited hearing disorders arise in childhood. Another set of symptoms are recurring gastrointestinal complaints, which the musician had already struggled with at a young age. However, there was no evidence of gluten or lactose intolerance or other diseases with a genetic cause, which have been repeatedly postulated in the literature as the cause of the complaints. In contrast, we found a very clear genetic disposition in the third symptom complex, the symptoms of liver disease. Through major genetic studies, we are now quite familiar with the factors that contribute to such a disease. In combination with Beethoven’s alcohol consumption and his hepatitis B infection, which was also detected for the first time in the study, we conclude that these were the main causes of liver cirrhosis.

Can cirrhosis of the liver explain Beethoven’s death?
Beethoven’s symptoms and the findings from his autopsy revealed that liver failure was the causative factor in his death. We have now found evidence that Beethoven had a significant genetic predisposition to developing cirrhosis of the liver. Based on such a predisposition, unfavorable external factors, such as alcohol consumption or infection with a hepatitis virus, can unleash their fatal effects much sooner.

How do you rank your results?
We were unable to prove any genetic causes for Beethoven’s hearing problems and abdominal complaints. However, this doesn’t mean that there may not be a connection between these symptom complexes. Beethoven’s genome data have now been published. This means research groups can use these data to conduct their own studies. Knowledge of the genetic causes of disease continues to grow, and new genes that contribute to the development of disease are being identified. It may well be that at least a partially genetic cause will be found for these symptom complexes in the future.

How reliable are your results?
Due to the age of Beethoven’s DNA, it is currently possible to make a reliable statement about around 55 percent of the genome. In addition to these sequenced regions, some neighboring regions of the genome can be inferred using statistical methods. However, this is still less in total than when blood is taken from a patient today and the genetic material is analyzed almost completely. New methods or DNA from additional samples could complete Beethoven’s genome in the future. Then there may also be new information on the previously inexplicable symptom complexes: for example, the hearing impairments and the gastrointestinal complaints.

Can scientific methods or results from this study be applied to other medical cases in human genetics?
Actually, it’s the other way around: We applied our findings from medical genetics to the case of Beethoven as an example. These data sets were not even available ten or 15 years ago. That’s why it was only now possible to arrive at such results. This shows the potential of such investigations: We can now use these methods to decipher individual disease stories like Beethoven’s step by step - as human genetic knowledge advances.

How do the results change the image of Ludwig van Beethoven?
The connection between physical constitution and artistic work is a very interesting musicological question. That’s where I reach my limits as a physician, but of course, we discussed this question. Exchange across disciplinary boundaries is an important goal of the project.

What is the biggest surprise from your point of view?
From a medical point of view, I find it very interesting how Beethoven’s example can be used to capture cirrhosis of the liver as an interaction of genetic and environmental factors. Both the genetic predisposition and the alcohol and viral infection go together here in a classic way in the sense of multifactorial disease development. I think it’s a great success to be able to work through this with a symptom complex like this.

The Stumpff Lock
The Stumpff Lock - in a laboratory at the Max Planck Institute for the Science of Human History, Germany. © Photo: Anthi Tiliakou
Labwork on the Moscheles Lock
Labwork on the Moscheles Lock - at the University of Tübingen, Germany. © Photo: Susanna Sabin
Prof. Dr. Markus Nöthen
Prof. Dr. Markus Nöthen © Photo: Barbara Frommann/University of Bonn

TJA Begg et al., ‘Genomic analyses of hair from Ludwig van Beethoven’, Current Biology (2023). DOI: 10.1016/j.cub.2023.02.041

Prof. Dr. Markus M. Nöthen, Direktor
Institut für Humangenetik, Universitätsklinikum Bonn
Phone +49 228 287-51100
E-mail: markus.noethen@uni-bonn.de

Dr. Axel Schmidt
Institut für Humangenetik, Universitätsklinikum Bonn
Phone +49 228 287-51276
E-mail: axel.schmidt@ukbonn.de

Beethoven House Bonn
Michael Forst
Phone +49 228 91254840
E-mail: m.forst@europressedienst.com

Max Planck Institute for Evolutionary Anthropology
Sandra Jacob
Phone +49 341 3550-122
E-mail: jacob@eva.mpg.de

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