Schizophrenia, a devastating mental illness that affects about one out of every 100 people, is known to have a large genetic component. But scientists have had little luck in finding genes that are responsible for large numbers of cases.  This in turn has hindered the search for new treatments that could provide relief to the tens of millions of schizophrenics worldwide.

But now new research has identified several common DNA variants that can influence the risk of developing schizophrenia. The key to this new success was data sharing - three large consortia combined their data to enable analysis of almost 13,000 people with schizophrenia and more than 34,000 controls.

All three research groups (SGENE, International Schizophrenia Consortium and the Molecular Genetics of Schizophrenia group) found that variants in a region of DNA that harbors multiple immune-related genes are strongly associated with schizophrenia.  Their results, published this week in Nature, fit with previous data suggesting that there is an autoimmune component to the disease.  These ideas stemmed from data showing that schizophrenics are more likely to be born in the winter or spring, the height of flu season.

As an example of one of these immune region variants, the SGENE analysis found that each C at rs3131296 increased the odds of schizophrenia by 1.19 times compared to someone with two Ts at this SNP.

The SGENE researchers associated two other variants with schizophrenia — rs12807809 in the NRGN gene on chromosome 11 and rs9960767 in the TCF4 gene on chromosome 18 —  that are known to be involved in brain development and cognition. These findings may open up avenues into research for new treatments able to address problems with decision-making and memory in ways that current schizophrenia medications do not.

The NRGN is expressed exclusively in the brain where it plays an important role in chemical pathways related to memory. Each copy of the more common T version of rs12807809 increased the odds of schizophrenia by 1.15 times compared to two copies of the C version.

The protein encoded by the TCF4 gene is essential for normal brain development.  Mutations in this gene have been associated with several disorders characterized by mental retardation.  Each copy of the C version of rs9960767 increased the odds of schizophrenia by 1.23 times.

(23andMe customers can check their data for all SNPs mentioned in this post by clicking on the “rs” numbers, which are linked to the Browse Raw Data feature.)

Last year, several studies suggesting that rare insertions and deletions in the DNA were common in schizophrenia cast doubt on whether genomewide association studies would ever identify common genetic variants associated with the disease. But the results of the International Schizophrenia Consortium show that there are in fact thousands of common variants that show at least some association with schizophrenia.  The authors say that although the effect of each individual variant is small, together they account for at least a third of the disease risk.

“Our results do not exclude important contributions of rare variants for schizophrenia,” the authors write. But their results do show that sequencing and studies of insertions and deletions cannot be the only methods used to study the genetics of schizophrenia. Further genomewide association studies of common variations will also need to be undertaken.

The International Schizophrenia Consortium analysis also found that many of the variations associated with schizophrenia are also associated with bipolar disorder, a finding at odds with the traditional view of psychiatrists that the two are distinct diseases.

“These new results recommend a fresh look at our diagnostic categories.  If some of the same genetic risks underlie schizophrenia and bipolar disorder, perhaps these disorders originate from some common vulnerability in brain development,” said Dr. Thomas Insel, director of the National Institute of Mental Health, in a statement.

“Of course the big question then is how some people develop schizophrenia and others develop bipolar.”

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Not many people could survive the harsh conditions of the Sahara Desert.  Yet the Tuareg have lived in the the region for millennia.

The Tuareg call themselves the Imazghan, meaning “free people.” Today they are known for a distinctive dark blue turban worn by the men, and for their long history as gatekeepers of the Sahara Desert. They are a semi-nomadic people who inhabit the West-Central Sahara, which encompasses parts of western Libya, Algeria, Mali, Niger, and some neighboring countries.

The Tuaregs were first mentioned by the ancient Greek historian Herodotus, who spoke of a group known as the Garamantes living in the Fezzan region of southwest Libya that operated trans-Saharan trade routes, connecting the heart of Africa to the North African coast. It is now believed that he was speaking of the Tuareg.

Though known to scholars since Herodotus’ depiction thousands of years ago, the Tuaregs remain shrouded in mystery. Their extreme isolation in one of the earth’s harshest environments has made them difficult for cultural anthropologists to study.  There have been only a handful of studies published on the Tuaregs’ genetic history, and even these examined only the genetics of western Tuaregs from Mali, Niger and Nigeria. The eastern Tuaregs who inhabit the Fezzan of Libya remain far less studied.  So a team of scientists decided to rectify this lack of genetic data, analyzing the mitochondrial DNA (mtDNA) of more than 100 Tuaregs from the Fezzan region of Libya. Their results are reported in the July issue of Annals of Human Genetics.

The authors chose to analyze the mtDNA for a variety of reasons, but mostly as a way of comparing their results to the previous genetic studies that had also used mtDNA. After extracting the DNA of the Tuaregs and assigning each individual to a specific maternal ancestry branch, or haplogroup, they found that the majority of Tuaregs fell into the same haplogroup: H1. In fact, over 61% of the individuals bore haplogroup H1.  This piqued the researchers’ interest, mainly because H1 is often thought to have spread with people from the Iberian peninsula across Europe after the end of the Last Ice Age about 12,000 years ago. The results of this study indicate that somehow H1 must have traveled into North Africa as well.

Not only did the researchers find that so many Tuaregs bear the same maternal haplogroup, but there was low genetic diversity among the population overall. This low genetic diversity can be tied to the fact that the Tuaregs are a very isolated people, and it is uncommon for them to venture too far outside their community when looking for a spouse. Indeed it seems that these Libyan Tuaregs are even genetically isolated from their West African counterparts, who showed far less European ancestry and far more ancestry tracing back to sub-Saharan Africa, despite the fact that both eastern and western Tuaregs share a common language and culture.

The authors have used these bits of information to piece together a scenario for the origins of the Libyan Tuaregs.  Environmental data reveal that, about 5,000 years ago, the Sahara was quickly shifting from its post-Ice Age period of relative stability and good living conditions to a less stable and more arid environment. This shift, the authors propose, was responsible for a series of human migrations throughout the Sahara that led different Tuareg groups living in the region to separate.  It caused other Tuareg groups to intermingle with neighboring groups.  Some Tuaregs, like those in Mali, Niger, and Nigeria, probably had more contact with sub-Saharan West Africans, which accounts for the higher percentage of sub-Saharan maternal haplogroups found by previous genetic studies.  Others, like the Libyan Tuaregs analyzed here, may have met and mingled with groups such as the Berbers of the Mediterranean coast of North Africa.  Apparently migrations from Spain after the Last Ice Age, across the Strait of Gibraltar into Morocco, brought H1 into the African continent. It then made its way into the North African Berber populations, eventually finding its way into the Libayan Tuaregs.

And what of the 35% of Libyan Tuaregs with sub-Saharan African genetic ancestry?  The authors of this study believe this to be a genetic signature of the trans-Saharan slave trade, which the Libyan Tuaregs famously operated during the 1st century BC, and which brought them to the attention of Herodotus so many years ago.

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On August 20, 79 AD, a series of small tremors and earthquakes began to shake the two ancient Roman cities of Pompeii and Herculaneum.  Lying in the shadow of Mount Vesuvius — about 150 miles south of the Roman capital — the two cities were often hit by tremors and earthquakes, so most residents were unperturbed.  After all, the tremors were relatively mild, especially compared to a severe earthquake that had hit both towns 17 years earlier.

They did not know, however, that this new string of tremors was in fact due to increasing pressure inside Mount Vesuvius; they did not know that Mount Vesuvius was in fact an active volcano; and they did not know that it was about to erupt.

Just four days later, on August 24, Vesuvius did just that.  The cities of Pompeii and Herculaneum were taken completely off guard.  So much so, in fact, that many residents were unable to escape the rain of pumice and ash that fell to dozens of meters high, burying people inside their homes.  Even those who did survive the ash were unable to outrun the pyroclastic flow, a wave of white-hot cinders that tumbled down Mt. Vesuvius at over 100 mph.  In just a few days, these cities became buried, and soon were forgotten.

Pompeii and Herculaneum remained buried for the next 1,600 years, when military engineers digging a new course for the River Samo uncovered what looked to be an underground city.  They had found the remains of the buildings, houses and plazas that made up these two ancient Roman cities.  And - perhaps more importantly - they found the remains of the inhabitants, often almost perfectly preserved.

This was especially true for the remains of 13 individuals, hidden inside a villa belonging to a Pompeii resident named Caius Iulius Polybius.  Inside the villa, two individuals were still holding hands; another was clutching her stomach, the remains of her unborn child still inside. Archaeologists have spent many decades trying to uncover as much as possible about these and the other thousands of individuals found buried in Pompeii and Herculaneum.  Now geneticists have entered the fray, using sophisticated techniques to extract and analyze the DNA of these 13 individuals with the goal of understanding the relationships between them.  The results of this analysis are published in the July issue of the the Annals of Human Genetics.

The research team, led by Giovanni de Bernado from the University of Naples, extracted the mitochondrial DNA (mtDNA) from all 13 individuals.  The mtDNA is passed down, almost always unchanged, from a mother to her children. So researchers can conclude that individuals in a grave or archaeological site who share similar or identical mtDNA profiles - known as haplogroups - are likely related to each other along the maternal line. The mtDNA is also useful in archaeology because it is more likely to remain preserved long after an individual dies.

But there can be problems with preservation when analyzing mtDNA, and that is exactly what happened with a few of the remains.  Di Bernado and his team were unable to extract mtDNA from three of the individuals.  But for the others, they were successful.  In fact, six of the individuals yielded an identical maternal haplogroup assignment:  T2b.  T2b exists in about 4-5% of modern Italians, making it one of the rarer haplogroups in the region.  So for it to exist at such high levels within a single household almost certainly proves some kind of familial relationship between the inhabitants of this house.

Who were the individuals bearing the T2b haplogroup?  Four children ranging in age from three to 14, a young woman of about 18 years, and a man of about 30 years. Di Bernado argues that the four children were probably siblings (or at least cousins), that the 18 year-old woman could perhaps be an older sister or aunt, and the man is likely to be a maternal uncle.  Unfortunately, one of the female remains - who would be an ideal candidate as the childrens’ mother, yielded no reliable mtDNA type.  The remaining individuals bore different haplogroups, and may have represented the father or paternal grandparents.  There is also the possibility that one of the adult women was a mistress of the head of the household, something not uncommon in ancient Rome.

For many years, the identities of the Pompeian and Herculanean victims’ remains, entombed in ash and cinders, have both haunted and intrigued scientists.  Now, with efforts such as the ones performed here by Di Bernado and colleagues, we are learning more about who they were in life, and not just about their final moments.

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Study after study has shown that high blood levels of C-reactive protein (CRP), a marker of inflammation, are associated with increased risk of cardiovascular disease. But what hasn’t been clear is whether CRP actually causes heart disease, or just indicates the presence of artery-blocking atherosclerosis.

Researchers from Imperial College London set out to answer this question using a genetic approach.  They reasoned that if high CRP levels really do cause heart disease then genetic variants associated with increased CRP should also be associated with increased heart disease risk.  Their results, published today in Journal of the American Medical Association, indicate that CRP might not be a key player after all.

Using a sample of 28,000 heart disease patients and 10,000 controls, Paul Elliott and colleagues examined several SNPs in the CRP gene. They found a significant association between the SNPs and CRP levels, and between CRP levels and heart disease — but not between the genetic variations and heart disease.

For example, each T at rs1205 lowered CRP by 20%.  Based on previous studies of CRP, this should have translated into 6% lower odds of heart disease. But there was no association of rs1205 with heart disease at all.

The researchers also identified four SNPs in other genes that were associated with CRP levels.  One was associated with heart disease in the expected direction (that is, the version associated with lower CRP was also associated with decreased heart disease risk). But two others had an inverse relationship with heart disease risk.  The final SNP affected CRP levels, but had no relationship with heart disease risk either way.

(The SNPs studied, their effects on CRP and heart disease risk, and other notes are included in a table at the end of this post.  23andMe customers will be able to check their data for three of the five SNPS addressed in this study.)

Medical Implications

The JUPITER trial, published in the New England Journal of Medicine in November, showed that middle aged men and women with low LDL cholesterol (below 130 mg/dL), but high CRP (greater than 2 mg/L) reduced their CRP levels by 37% and cut their risk of heart attack by 54% by taking rosuvastatin (Crestor®).

These results suggest that CRP should be taken into account when deciding whether to prescribe statins to a patients, a move that would result in millions more Americans taking the drugs.

But the results of this new genetic study suggest that lower CRP doesn’t necessarily translate into a lower heart disease risk.  These findings support skeptics of the JUPITER trial, who argued that the improvements in cardiovascular disease risk seen with rosuvastatin treatment could have been due solely to their reduction (50%) of the study participants’ already low cholesterol levels.

But the new study doesn’t necessarily mark end of the road for CRP testing.  In an editorial accompanying the new report in JAMA, Svati Shah and James de Lemos argue that even if CRP does not cause heart disease, it might still be valuable as a marker for identifying people who are at risk but do not exhibit traditional indicators such as high cholesterol.

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Much to the surprise of many scientists, a lot of the SNPs identified in genomewide association studies have not been in the parts of genes that encode the molecular machinery of a cell.

Instead, many SNPs have been found on the edges of genes, in regions of DNA that control when the genes get turned on or off, in parts of genes that get cut out before the final proteins are made, or even in so-called “gene deserts,” areas of DNA that don’t seem to contain any genes at all.

Rs6983267 is one of these gene desert SNPs.  People with two copies of the G version of this SNP have about 1.4 times the odds of developing colorectal cancer compared to people who have two Ts, but so far no one has been able to figure out why.  Two new reports show that, even though this SNP seems to be out in the middle of nowhere in the genome, it can interact with components of a signaling pathway known to be overactive in more than 90% of all colorectal cancers.

(23andMe customers can see their data for rs6983267, as well as two other SNPs associated with increased colorectal cancer risk, in Health and Traits.)

Results from Tuupanen et al. and Pomerantz et al., both published online this week in the journal Nature Genetics, show that the region of DNA containing rs6983267 is an “enhancer” that can turn up the amount of protein made from the MYC gene. The riskier G version of the SNP appears to make the enhancer stronger than the T version.

In colorectal cancer, increased MYC expression can often be traced to overactivity of a molecular signaling pathway known as Wnt.  Both groups of researchers found that the region of DNA containing rs6983267 was responsive to Wnt signaling, thus connecting this SNP to a well-established cancer mechanism.

Drugs that attack the Wnt pathway are attractive candidates for cancer therapies.  According to Tuupanen et al., the new results suggest that these same types of drugs might be useful for personalized cancer prevention treatments in people who carry the riskier version of rs6983267.

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Not surprisingly, there has been intense interest in the genetics of obesity in recent years.  Obesity is a major health problem, resulting in tens of thousands of premature deaths and billions of dollars in healthcare costs each year in the United States, and it is known from twin and family studies that weight is a highly heritable trait.

The genetic mutations and variations identified so far explain only a small percentage of the variability in body mass seen in the population.  Some exciting clues have been found, however, as to why some people are more prone to obesity than others and how this might be counteracted.  But new research, published online this week in the American Journal of Human Genetics, shows that caution must be taken in moving from genetic discoveries to drug development.

Variations in the FTO gene have consistently been associated with obesity. On average, people who carry two copies of the “risky” version of this gene weigh six to eight pounds more than those who carry none. Mice completely lacking the FTO gene were shown to be leaner than their normal littermates, despite being less active.  These results have led some to suggest that inhibiting the FTO protein with a drug could be a good for obesity treatment or prevention.

(23andMe customers can see their FTO data in the Obesity Research Report.)

But an international team of researchers led by Sarah Boissel of the Université Paris Descartes in France has found that a mutation that interferes with the function of the FTO protein is associated with a lethal genetic condition.  Members of a large, inbred Palestinian family born with two copies of this mutation had multiple developmental abnormalities and died before the age of three.  Based on their results, Boissel and her colleagues warn that any research exploring the use of FTO inhibitors as obesity treatments must include a “careful assessment” of the potential to cause birth defects and other toxic side effects.

More about FTO:

SNPwatch: Gene Variant Linked to Obesity Affects Food Choices in Children

It’s Not Genes or Environment, It’s Genes AND Environment

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It’s not enough to teach genetics, says Michael Dougherty, director of education for the American Society for Human Genetics.  It has to be taught in the right way.

“Current teaching practices may be producing a public that is unprepared to participate effectively as medical consumers in a world where personalized medicine will rely increasingly on genetic testing, risk assessment, predispositions, and ranges of treatment options that include biological and behavioral components,” writes Dougherty in an opinion piece published online today in the American Journal of Human Genetics.

Dougherty calls for curriculum reform at all levels, from middle school all the way up through undergraduate education. The key, he says, is for students to understand that the genetics of most human traits and conditions are complex and, with only rare exceptions, not deterministic.

Dougherty suggests a new genetics curriculum that begins with lessons on traits that show continuous variation, such as height and weight, and focuses on how multiple inherited and environmental factors can affect these traits.  Teachers could then move on to discussions of genes and the molecular details of how they are passed from generation to generation.  Only here, in the later stages of their genetics education, would students learn about the rare single gene diseases, such as cystic fibrosis and PKU, that make up the bulk of today’s genetics lessons.

“Our incompleteness of understanding and the messiness of complex-trait examples are poor arguments for maintaining the status quo in our genetics classrooms.  We know on theoretical grounds that the entirety of phenotype is defined by genes and environment, and substantial uncertainty still characterizes both.  To pretend such uncertainty does not exist is to deprive students of an appreciation of both modern genetics and the nature of science.”

Dougherty points to the Genes, Environment and Human Behavior module, funded by the Department of Energy and available from BSCS, as an example of the kind of lesson that could help correct the misconceptions that students already have.  The National Human Genome Research Institute also has available a Human Genetic Variation curriculum supplement.  And of course, you can always check out the Genetics 101 section of the 23andMe website for a basic introduction to genetics.

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Malaria, a strong evolutionary pressure in humans, has also shaped the baboon genome, new research says.

Each year at least 350 million people around the world are infected by malaria parasites.  More than one million people, mainly young children, succumb to the disease.  But these numbers would be even higher if it weren’t for genetic adaptations that have evolved in populations living in areas where malaria is a common threat.

Populations in Africa, Papua New Guinea and Brazil, for example, carry variations in the DARC gene that protect them from infection by the P.vivax malaria parasite.  DARC encodes the Duffy antigen, a protein exploited by P.vivax to enter red blood cells. The protective variations prevent expression of the Duffy antigen by the DARC gene, leaving the parasite without a mode of entry to establish an infection.

Wild baboons are not usually infected by P.vivax or other malarial parasites that affect humans, but they are vulnerable to several closely related species.  In a new report, Duke University researchers show that, like some humans, groups of yellow baboons from Kenya’s Amboseli National Park carry variants affecting DARC gene expression that provide protection against malaria. These findings, published this week in the journal Nature, mark the first time that a genetic variation has been linked to complex trait in a wild non-human primate population.

While the genetic variations that produce P. vivax malaria resistance in humans turn the DARC gene off, the variations that protect baboons from malaria actually increase the amount of protein made from the gene.  This suggests the mechanisms of resistance to malaria infection are different between the two species.  Researchers, however, are still impressed with the parallel nature of these evolutionary adaptations.

“It’s a nice example of how – in the vastness of the genome – the same gene was modified in the same way in two different species to produce the same kind of resistance,” Greg Wray, senior author of the report, said in a statement.  “That’s a pretty remarkable thing when you think of all the different ways malaria resistance might have evolved.”

Gathering the data for this study was no easy feat.  Graduate student Jenny Tung, lead author of the report, spent three summers in the East African savanna collecting DNA-laden baboon feces and darting animals in order to take blood samples.  Wray says that the success of her work shows the power of combining fieldwork and genomic analysis.  According to him, the next challenge will be to understand how genetic variation contributes to complex behavioral traits like social status and aggression in wild primates.

(23andMe customers can see what their data says about variations associated with malaria resistance in the following Health and Traits articles: Malaria Resistance (Duffy Antigen), Sickle Cell Anemia & Malaria Resistance and G6PD Deficiency.)

Photo: Paul Mannix/flikr

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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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Each one of us carries in our cells the vital genetic data, compliments of our parents, that code for many of our traits and attributes.  Whether it’s our eye color, height or the ability to consume dairy products, the variations in our genes contribute to making us ‘one of a kind’.  Unfortunately, these variations can also lead to the onset of disorders that aren’t so unique.

Technology now allows scientists to tap into our DNA as they attempt to unlock the underlying genetic causes of diseases that afflict so many of us.  These studies, often called Genome-Wide Association Studies (GWAS) because of their comprehensive design, are producing some very compelling results. Under the present research model, individuals who are asked to consent to participating in these studies typically donate a blood or saliva sample and provide access to information about their particular disease (or drug response, in the case of pharmacogenetic studies) through their health records or through diagnostic interviews.  Scientists then look for genetic correlations that can help direct the development of diagnostics and therapeutics.

This model is fairly steeped in tradition and protocol.  Once your sample and information are collected, researchers go out of their way to break the link back to you, with the mindset that it’s a necessary measure to protect your privacy — and, frankly, minimize their liability to deliver and explain the data. The genetic information derived from your DNA is often “de-identified” or “anonymized” so that it can’t be traced back to you.  As a “human subject” in a study such as this, you are not offered access to this very personal data.  Yet it could be very important for you to know. Now that we have more knowledge about how our genes impact our lives, thanks to these very studies, shouldn’t you be given access to the data if you want it? Even if there’s little you can do to alter the course of your genetic predispositions — which are often not definitive — we’re seeing overwhelming evidence that a lot of people would like this information.

At 23andMe, we believe it’s time for a research revolution, where the people involved — let’s no longer call them human subjects — can play a more active role and contribute more directly to studies of most interest to them and their families.  And if any individual would like access to his or her data, he or she should be granted that request.

In this spirit, 23andMe is proud to support www.HealthDataRights.org and the Declaration of Health Data Rights.  We believe genetic data are an integral part of your health information, and you should have access if you so choose.

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