Leprosy is a chronic, disabling disease caused by a bacterium (Mycobacterium leprae) that infects only humans and armadillos. The disease affects the skin and peripheral nerves, leading to sores, numbness in the limbs, muscle weakness, and, in severe cases, disfiguring nodules on the skin. Known since biblical times, leprosy was highly stigmatized until the latter part of the 19^th century, when the Norwegian doctor Gerhard Hansen discovered that it was caused by a microorganism.

Although multi-drug therapy has cured millions of people of leprosy in recent decades, hundreds of thousands of new cases still occur per year, mostly in developing countries. Finding a way to eradicate the disease is therefore considered important for reducing the number of preventable disabilities worldwide.

Because Mycobacterium leprae is specific to humans and cannot be grown in lab dishes, research into factors influencing disease susceptibility and clinical outcomes has been limited. But the host environment as well as the bacterium itself can affect the course of the disease; in other words, human genetic factors may play an important role in determining who is more susceptible to infection. Since leprosy has been shown to cluster in families, scientists suspect that much of the variability in disease susceptibility and symptoms stems from diversity in individual human immune systems rather than differences between and within strains of the bacteria.

In a new study published today in New England Journal of Medicine, a team of researchers reports new human genetic factors associated with susceptibility to leprosy in Asians. Led by Fu-Ren Zhang of the Shangdong Academy of Medical Sciences in China and Jian-Jun Liu of the Genome Institute of Singapore, the scientists tested 93 variants across an estimated 50 genes in 3254 Chinese individuals with leprosy and 5955 Chinese individuals without the condition. Their analysis identified variants in seven of these genes to be significantly associated with leprosy.

“The discovery of these genes is a major breakthrough for research in leprosy and infectious diseases in general, and will be significant in the early diagnosis and development of new treatments,” said Dr. Liu in a press release.

The strongest of the associations were rs602875 in HLA-DR-DQ, rs3764147 in C13orf31, and rs9302752 in NOD2. In addition, some of the genetic variants were more strongly associated with a form of leprosy that results in more severe symptoms, known as the multibacillary form. These included rs9302752 in NOD2 and the variant rs1491938 in LRRK2.

(23andMe Complete Edition customers can check their data for SNPs reported in this study using the Browse Raw Data feature. See table at the end of this post.)

Altogether, five of the seven genes identified in the study could be shown to interact biologically in the context of immune response to infection. Two of these five genes, NOD2 and TNFSF15, harbor genetic variants that are also associated with Crohn’s disease (see 23andMe’s report on this condition). Crohn’s manifests some common features with leprosy at the cellular level and other researchers have suggested that mycobacterial infection may be a risk factor for Crohn’s. The findings reported by Zhang and Liu and their colleagues provide additional evidence for shared disease mechanisms between Crohn’s disease and leprosy and may increase the range of treatment options for both conditions.

Variants significantly associated with leprosy in individuals of Asian ancestry

* As reported on the 23andMe website through the Browse Raw Data feature.

** Effect only applicable to the multibacillary form of leprosy. LRRK2 is better known as a susceptibility gene for Parkinson’s disease (see 23andMe’s report on this condition). Interestingly, PARK2, another gene linked to Parkinson’s, was associated with leprosy in earlier studies. The reason for the connection between Parkinson’s and leprosy is unclear, though researchers have speculated that some of the same treatments may be effective for both conditions.

SNPwatch gives you the latest news about research linking various traits and conditions to individual genetic variations. These studies are exciting because they offer a glimpse into how genetics may affect our bodies and health; but in most cases, more work is needed before this research can provide information of value to individuals. For that reason it is important to remember that like all information we provide, the studies we describe in SNPwatch are for research and educational purposes only. SNPwatch is not intended to be a substitute for professional medical advice; you should always seek the advice of your physician or other appropriate healthcare professional with any questions you may have regarding diagnosis, cure, treatment or prevention of any disease or other medical condition.

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Genomewide association studies have had some success in finding DNA variants associated with increased risk for bipolar disorder.  But researchers from the MRC Centre for Neuropsychiatric Genetics and Genomics at Cardiff University in England have taken these studies a step further by looking for common functional themes running through the GWAS data. Their results, published online this month in the American Journal of Human Genetics, implicate some of the most basic biological pathways in the genesis of bipolar disorder.

Starting with the idea that the genetic variations increasing risk for a disorder are probably not randomly distributed throughout the genome, but instead are in one or more sets of related genes, Holmans et al. re-analyzed the SNP data from four previous studies that included a total of 4,387 cases of bipolar disorder and 6,209 controls. Researchers at the Children’s Hospital of Philadelphia recently took a similar approach (although the technical details of the analysis differ) for a study of Crohn’s disease.

The bipolar disorder researchers found that biological pathways involved in broad control of cellular activity were overrepresented in the genetic variations association with bipolar disorder.  Two of the pathways, hormone activity and cellular self-digestion, are known to be impacted by lithium, the major medication used to treat bipolar disorder. As always, more research will be needed to substantiate these findings, as well as to understand how they can be used to help the more millions of people worldwide dealing with bipolar disorder.

(23andMe customers can learn more in the Bipolar Disorder Research Report and the Bipolar Disorder: Preliminary Research Report.)

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Throughout the course of human evolution, there have been plenty of firsts. Small changes in our genetic code have laid the groundwork for our bipedal gait, our large brains, and our ability to speak complex languages.

There are countless genes throughout the human genome that distinguish us from our evolutionary relatives; now scientists have found yet another example. However, unlike novel and uniquely human mutations like FOXP2 and MYH16, this gene has been nestled in suspended animation within our genomes for tens of millions of years: it just needed a wake-up call. In this week’s issue of PLoS Genetics , an international team of scientists investigates this gene’s unique history.

Their analysis centers on a family of genes known as Immunity Related GTPases (or, IRG). Most mammals have many copies of these types of genes, which play a vital role in helping the immune system resist pathogens like bacteria. But humans and our closest relatives – the Great Apes – have one IRG gene, IRGM. Yet our slightly more distant relatives, such as the monkeys, have no working copies of IRGM, or any other members of the IRG gene family.

How could it come to pass that we and the apes share more in common with mice – at least in terms of IRG – as opposed to other primates? That apparent discrepancy turned out to be central to understanding the genetic history of IRGM.

The answer, according to the geneticists, was relatively simple: When looking at the evolution of our species, going back tens of millions of years, it is clear that IRGM was never ‘erased’ from our genomes. Instead, it simply laid dormant, and it was not until the common ancestor of apes and humans split off from monkeys that IRGM awoke from its long slumber.

The exact reason that IRGM was reborn in species such as humans and apes, but not monkeys, is not yet completely understood. We do know, however, that the fact that most humans have a working copy of IRGM is quite fortuitous. As mentioned above, the IRG genes are essential to controlling bacteria, specifically by maintaining the delicate balance of bacterial growth and immune control in our intestines. Recent research has shown that those without a working copy of IRGM have a greater risk of developing Crohn’s Disease, in which an individual’s immune system begins attacking the friendly bacteria living in our guts. The results are chronic – and painful – digestive problems. Without a doubt, IRGM is beneficial to the health and well-being of our digestive system, and its role in decreasing the risks of Crohn’s Disease cannot be underestimated.

Beyond shedding light on the practical value of IRGM, this study has revealed the first instance of a gene being ‘reborn’ after lying dormant for millions of years. As the study’s team leader, University of Washington professor of Genomic Sciences Evan Eichler put it, “These findings tell us we shouldn’t count a gene out until it has been completely deleted.”

How many other resurrected genes are sprinkled throughout the human genome? As the field of genetics explores the hidden depths of our genomes, we can only begin to wonder how many similar discoveries await.

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Genome wide association (GWA) studies of SNPs are helping scientists learn about the underlying biology of many complex diseases. But even the most enthusiastic proponents of this relatively new type of research admit that many studies simply can’t find genetic variations that have real, but very small, effects.  This means information that might be useful for diagnosis, prevention or treatment of a disease is being left on the table. The 23andMe research initiative, 23andWe, is one way of addressing this problem.

Researchers from Children’s Hospital of Philadelphia have devised a different method.  Instead of focusing on individual SNPs, they are grouping SNPs together by gene pathway — collections of genes known to work together – and using sophisticated mathematics to identify those groups that appear to be related to disease status.

Using this approach, the researchers have identified the IL12/IL23 pathway — a collection of genes involved in regulating the immune system – as important in Crohn’s disease. Their results, published online today by the American Journal of Human Genetics, not only show the utility of their new method, but may point the way toward the development of new treatments for Crohn’s disease.

“Our study suggests that examination beyond individual SNP hits, by focusing on genetic networks and pathways, is important to unleashing the true power of GWA studies,” the authors write.

The researchers used data from four previous GWA studies for their analysis.  Three of the studies were done in people with European ancestry, and the fourth was a small study of African Americans.

“Despite the drastically different association results on the level of individual SNPs across studies, the [IL12/IL23] pathway was consistently picked up as being associated with CD [Crohn’s disease] in all four GWA studies, demonstrating the power and effectiveness of pathway association approach in identifying disease-susceptibility mechanisms,” the author’s write.

It is not completely surprising that the IL12/IL23 pathway was identified as being involved in Crohn’s disease in this study.  Several genes from the pathway have previously been linked to Crohn’s disease through GWA studies.  Treatments that inhibit the protein encoded by the IL12 gene can reduce symptoms in people with Crohn’s disease, in some cases putting them into complete remission.  The authors say that their analysis suggests that more members of this gene pathway – including genes that might never be picked up in a standard GWA study – could also be promising therapeutic targets for the disease.

23andMe customers can learn more in the Crohn’s Disease Clinical Report.

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In the year 1831, two very important events happened to 22 year-old biologist Charles Darwin.  The first was that he boarded the Beagle, a research vessel upon which he would embark on a five-year journey to Central and South America.  There he would collect mountains of data on hundreds of plant and animal species, which he would then use to develop his theory of evolution by natural selection — the cornerstone of modern biology.

The second event was that — just before boarding the Beagle — he fell extremely ill.  Darwin kept his condition secret for fear of being removed from the passenger list.  But this early bout of illness was just the beginning in a series of ailments that would continually affect nearly every aspect Darwin’s life for the next 40 years.

The list of symptoms that plagued Darwin for the majority of his adult life included everything from chronic fatigue, severe abdominal pain, nausea and vomiting, headaches, insomnia, mouth ulcers, boils, anxiety, heart palpitations, and depression (just to name a few).  In his many letters to friends and colleagues, he constantly mentioned the wretched state of his health.  In 1865, he wrote to noted naturalist and friend William Hooker, “I have been [for] five or six wretched days miserable from morning to night and unable to do anything.”  Just a year earlier he had told Hooker, “for five months I have done nothing but be sick.”  His illness often precluded him from many public lectures and events expected of eminent scientists of the time.  His wife, Emma, tried to care for Darwin, as did numerous physicians, but his poor health remained until his death in 1882.

The importance of Charles Darwin as a father of modern biology, combined with the complex and intriguing nature of his chronic illness, have led to many hypotheses as to why he suffered as he did.  Everything from heart disease to arsenic poisoning to a variety of psychosomatic causes have been proposed since his death.  However, it is only within the last several years that these hypotheses have focused on the gastrointestinal symptoms that seemed to plague Darwin most consistently.  Unable to examine the man himself, scientists have pored over his medical records, letters, and personal diaries, in order to posthumously diagnose Darwin’s debilitating illness.

The Case for Lactose Intolerance

During the mid-19th century, lactose intolerance had not yet been described in great detail.  Most gastrointestinal problems were written off as ‘indigestion’ or ‘dyspepsia’.  Indeed, the genetics of lactose intolerance would not be discovered until more than 70 years after Darwin’s death.

People diagnosed as lactose intolerant often suffer severe lower abdominal cramping and diarrhea after consuming milk or other dairy products (including some cheeses and various kinds of cream). Because the majority of Darwin’s symptoms appear to be centered around the digestive tract, a group of researchers from Cardiff University proposed in 2005 that the best explanation for Darwin’s symptoms was lactose intolerance.

It is far more common to find lactose intolerance among South and East Asian populations, though it is not unheard of to find it among Europeans, where it reaches levels of about 8%.  Researchers, digging through his written correspondence, have found many key passages that hint at Darwin being lactose intolerant. For example, in 1865, Darwin wrote to H.B. Jones, his physician, recounting that “on most days, three hours after luncheon or dinner I have a sharpish headache on one side, and with bad flatulence last to the next meal.”  He also wrote to his friend and colleague, William Hooker, “I have had a bad spell.  Vomiting everyday for eleven days, and some days after every meal.”

An analysis of his Diary of Health indicates that foods such as sugar, bacon, butter, and any desserts seemed to intensify his symptoms.  Unfortunately Darwin had a sweet tooth, and the majority of his wife’s recipes involved heavy cream.  To make matters worse, when Darwin was feeling particularly ill he was often given warm milk as a nightcap, a typical remedy during the mid-19th century.  This may have exacerbated his abdominal pain and discomfort.

In fact, the only treatment that appeared to work was something called “hydrotherapy” in which the patient bathed and drank copious amounts of cold water.  Milk was not allowed.  This, some argue, is additional evidence in support of lactose intolerance being the primary cause of Darwin’s symptoms.

The Case for Crohn’s Disease

However, while most agree that the majority of Darwin’s symptoms were gastrointestinal in nature, some remain unconvinced that the best explanation was that Darwin was lactose intolerant.  Instead, they point to a more serious disorder known as Crohn’s Disease.  This new diagnosis is garnering much support within the medical community, in that Crohn’s – even more so than lactose intolerance – accounts for the vast majority of Darwin’s incapacitating symptoms.

Crohn’s disease is a chronic autoimmune disease of the digestive tract.  It is found in about 1-2% of people of European descent, and can affect an individual’s entire digestive system, from the mouth to the anus and everything in between.  Additional symptoms include skin rashes, arthritis, and inflammation of the eye.  It usually first presents itself in early adulthood as a severe gastrointestinal infection.  Individuals suffering from the disease often have a series of flare-ups and remissions throughout their lives.  Crohn’s disease is believed to be a largely genetic disorder, though not all genetic markers have been identified.

Various factors can influence the timing and frequency of flare-ups for sufferers of Crohn’s, including stress, nutrition, and other health issues.  Indeed, Darwin often noted worsening symptoms during periods of high stress, especially when he had to give public appearances or lectures.

Upon close examination of Darwin’s correspondence and diaries by scientists at the University of Chile, his most severe symptoms included abdominal pain and vomiting, but virtually no mention of diarrhea, which is the main symptom of lactose intolerant individuals.  In fact, Darwin had reported regular bowel movements for the majority of his adult life.  It was the abdominal pain, nausea, and vomiting that plagued him for so many years, and these symptoms are key when diagnosing Crohn’s Disease.

In addition, and perhaps more importantly, Darwin had several other health issues seemingly unrelated to the digestive tract, namely skin and eye irritation. Symptoms such as these are often found in patients diagnosed with Crohn’s Disease.  And the fact that there are conflicting reports on the kinds of foods that upset his illness (Darwin also reported getting sick after eating sugar, bacon, and salads), lends additional support that his illness was not related to a specific type of food (i.e. dairy).

There is, of course, the possibility that Darwin suffered from both lactose intolerance AND Crohn’s Disease.  In fact, there is an 83% chance that individuals with Crohn’s Disease are also lactose intolerant.  However, the reverse is not also true, meaning the root cause of lactose intolerance among people with both conditions usually traces back to their Crohn’s.

It also appears that there is some genetic aspect to Darwin’s illness, as many of his family members suffered chronic health problems.  In fact, the Darwin family was famous throughout the 19th and early 20th centuries as having overall poor health.  Darwin’s family history points to some kind of genetic disorder, and the symptoms of Crohn’s disease appear to be the most comprehensive explanation.

The mystery surrounding Darwin’s chronic illness has mystified researchers for over 100 years.  If he were alive today, it is likely that physicians would have no trouble diagnosing what ailed him. And it’s too bad Darwin couldn’t sign up for 23andMe’s Personal Genome Service ^TM! Not only would the father of modern biology be fascinated by his genetic data, but it might have offered a clue to his lifelong illness as well by revealing whether he had a higher risk for lactose intolerance, Crohn’s Disease, or perhaps some other condition.

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Just about every week a new genome-wide association study links common variations in the genome to some disease. But only rarely do the authors of these studies have more than a guess of why these SNPs are associated with a particular condition.

On Sunday in the online edition of Nature Genetics, researchers presented results that may bring them closer (though not all the way) to understanding one SNP recently associated with Crohn’s disease.

Each copy of a C at rs13361189 increases a person’s risk of developing Crohn’s disease 1.33 times compared to someone with two copies of a T. This SNP lies very close to IRGM, a gene for a protein involved in clearing out bacteria that invade cells. A SNP in another gene involved in this same process, known as autophagy, has also been linked to Crohn’s disease.

(23andMe customers can check their data at substitute SNP rs7714584. The G version is linked with an increased risk for Crohn’s disease.)

It makes sense that genes involved in autophagy would influence a person’s risk for Crohn’s, because the body’s ability deal with bacteria in the intestines is thought to be at the heart of this inflammatory bowel disease. Yet studies have failed to find anything in the IRGM gene itself that could account for this particular SNP’s association with Crohn’s.

McCarroll et al show in their current study that people with the C version of rs13361189 also have a large deletion of about 20,000 DNA bases in front of the IRGM gene that people with the T version (A for 23andMe customer’s looking at their data for rs7714584) don’t have.

The deletion appears to regulate how much protein is made from the IRGM protein, although exactly how it does this is not clear. In laboratory tests the deletion caused some cell types to make more protein, while others made less.

The researchers can’t say which direction the deletion is working in the intestines, but they do know that the amount of IRGM protein affects cells’ autophagy abilities. Lab tests also showed that cells with more IRGM are better able to engulf and destroy invasive bacteria compared to cells with less.

More research will be needed to fully understand the meaning of variations in the IRGM gene, as well as the more than thirty other SNPs so far associated with Crohn’s. As scientists begin to understand the functional consequences of the variations, they will gain valuable insight into the mechanisms of the disease that may some day lead them to new and better treatments.

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