Even if you do everything right – exercise, healthy eating, no smoking– whether or not you’ll make it to the century mark depends to some extent on your genes.

One of the important longevity genes seems to be FOXO3A.  It’s been linked to lifespan in several experimental animal models. In humans, studies have shown that certain variations in the FOXO3A gene increase the odds of being extremely long-lived.

(See SNPwatch: Mounting Evidence That FOXO3A Contributes To Human Longevity for more about FOXO3A variation and, for 23andMe Complete Edition customers, a link to your data.)

It’s not exactly clear how FOXO3A affects longevity because it’s known to play a part in several important cellular functions, including cell growth, cell specialization, response to oxidative stress and  the regulation of cell death.  Two studies published last month in the journal Cell Stem Cell added to the list of the FOXO3A’s talents.  Renault et al. and Paik et al. showed that in mice FOXO3A and related FOXO genes are involved in maintaining the brain’s ability to generate new cells, a function critical for both normal brain functions and repair in response to natural degeneration or injury.

New brain cells arise from a pool of specialized self-renewing cells called neural stem cells.  The FOXO genes appear prevent the brain from burning through its supply of these important cells prematurely.

“Because [neural stem cells] have been shown to be important for learning, memory, and mood regulation, our findings could give insight into the decline in cognitive function that occurs during aging,” Renault et al. wrote in their report.

More research will be needed to fully understand the role of the FOXO genes in neural stem cells.  Experiments will also be needed to test whether these findings can be extended to humans.

Despite the work that is left to be done, Paik et al. optimistically suggest the new understanding of the importance of the FOXO genes in neural stem cells may help guide the development of drugs that could help improve central nervous system health in the elderly and people suffering from neurodegenerative disease or brain injury.

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Despite years of effort and millions of dollars in research funding, only one gene, APOE, has been conclusively associated with Alzheimer’s disease risk so far.  But now the results of two of the largest Alzheimer’s studies ever provide convincing evidence that three more genes affect risk for the disease.

“These findings are a leap forward for dementia research.  At a time when we are yet to find ways of halting this devastating condition, this development is likely to spark off numerous new ideas, collaborations and more in the race for a cure,” said a statement from Rebecca Wood, Chief Executive of the Alzheimer’s Research Trust in the UK.

A British team, led by Julie Williams, found strong evidence that rs11136000 in the clusterin gene and rs3851179 in the PICALM gene are both associated with risk for Alzheimer’s. For both SNPs, each copy of the less common T version decreased the odds of having late-onset Alzheimer’s by 0.86 times compared to two Cs.

(This is correct. The versions and effects of the two SNPs really did turn out to be exactly the same.  23andMe customers can check their data for both SNPs using the links to the Browse Raw Data feature above.)

A French team, lead by Philippe Amouyel, also found strong evidence for an association between rs11136000 and Alzheimer’s risk, and suggestive evidence for an association with rs3851179.

In addition, Amouyel’s research revealed that the A version of rs6656401 in the CR1 gene increases the odds of Alzheimer’s by 1.21 times. Suggestive evidence for this association was also seen in the work of Williams’ group.

(23andMe cannot offer information about rs6656401 at this time.)

The results from both teams were published online this week in the journal Nature Genetics.

Williams said in a statement that the number of people who fall victim to Alzheimer’s could be reduced by 20% if treatments addressing the effects of the three newly identified genes could be found.

The proteins made by the clusterin and CR1 genes are known to play a part in clearing out amyloid beta, the protein that forms plaques in the brains of people with Alzheimer’s.  PICALM encodes a protein important for proper communication between brain cells, a process that is known to be disturbed in Alzheimer’s patients.

In total, the DNA of more than 10,000 people with Alzheimer’s disease and more than 18,000 controls from ten countries was analyzed by the two teams of researchers.  But both groups agree that there is still much more to find.  Williams’ team is already planning an even larger study involving 60,000 people that she believes can be completed within the next year.

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Alzheimer’s, the most common cause of dementia in people 65 years and older, currently affects about five million people in the United States. As the population ages, many more people are expected to be afflicted; some estimate 14 million Americans will have Alzheimer’s by the year 2050.

(For technical reasons, 23andMe cannot currently give customers information about their APOE status.  Our scientists are actively working on this problem.)

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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The benign and malignant forms of neuroblastoma may have different genetic underpinnings, a new study published online this week in Nature Genetics suggests.

Neuroblastomas develop from primitive nerve cells in an embryo or fetus and are one of the most common solid tumors in childhood.  They generally occur in infants and very young children and are rarely found in children over the age of 10.  In many cases the tumor is easily treated or disappears on its own.  But about 50% of the time the cancer spreads throughout the body.  Unfortunately, only about 35% of children with this aggressive form of the disease survive, despite intense treatment.

Recent work showed that DNA variations on chromosome 6 are associated with neuroblastoma, and, more specifically, with the aggressive form of the disease.  In this latest study, the same research team that found the chromosome 6 SNPs further investigated the possibility that different forms of neuroblastoma have different causes.

The scientists compared DNA from about 760 people with high-risk, aggressive neuroblastoma to more than 4,100 disease-free controls and identified several SNPs within the BARD1 gene on chromosome 2 that are associated with the most serious form of disease.  Additional analysis showed that one SNP alone, rs3768716, could account for the effects they saw.  Each copy of a C at this SNP increased the odds of aggressive neuroblastoma by 1.68 times.

When the researchers went back and analyzed DNA from a collection of low- and intermediate-risk neuroblastoma cases, they found that there was no association with rs3768716.

“Our data suggest that genetic initiating events may predispose not only to cancer, but to a particular subphenotype of the disease, and thus to disease outcome.  This may have implications for both screening and identifying critical pathways for targeted therapeutics,” the authors write.

The protein encoded by the BARD1 gene binds to the BRCA1 protein and is considered to be essential for the latter’s ability to keep cells cancer free.  But although mutations in the BRCA1 gene are a known risk factor for breast cancer, BARD1 mutations have not been implicated in that disease.  The association of variations in the BARD1 gene with neuroblastoma reported in this study is the first evidence that this gene is involved in cancer susceptibility.  The authors say that ongoing studies are now focusing on how the SNPs they identified affect the BARD1 gene and ultimately cancer development.

(23andMe customers can see their data for one of the previously reported SNPs on chromosome 6 in the Neuroblastoma Research Report. The Browse Raw Data feature can be used to see data for rs3768716.  According to the authors of this study, the two SNPS independently affect the odds of having neuroblastoma.)

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New genetic evidence adds strength to the theory that abnormal connections between brain cells are at the root of autism.

Autism is just one of the autism spectrum disorders (ASDs), a group of childhood developmental disorders that cause impairments in verbal communication, social interaction and behavior.  An estimated one in 150 children in the United States is affected.  Studies have indicated a strong genetic contribution to ASDs, but only a few rare genetic risk factors have been identified so far.  Now two reports, published online today by the journal Nature, demonstrate an association between the risk for autism and common genetic variants in and around genes that affect how brain cells migrate to the correct places in the brain and adhere to one another.

“Although we cannot immediately apply this research to clinical treatment, these findings increase our understanding of how autism spectrum disorders arise, and may in time foster the development of strategies for prevention and early treatment,” said Susan Levy, a co-author of both studies.

A large research team, led by Hakon Hakonarson of Children’s Hospital of Philadelphia and including scientists from more than a dozen research institutions, analyzed DNA from more than 10,000 people with European ancestry, including people with autism, their families and volunteers from the community.  They found several SNPs associated with autism.  All were located in a region of DNA between two genes, CDH9 and CDH10, which encode proteins called cadherins.

“These molecules are expressed on the cell surfaces of neurons, and they are involved with shaping both the physical structure of the developing brain and the functional connections among different brain regions.  Although a particular gene variant may contribute a small risk for an ASD in a particular individual, we estimate that the variants we discovered may contribute to as many as 15 percent of ASD cases in a population,” said Hakonarson in a statement.

The strongest signal came from rs4307059 — compared to two copies of a C, each copy of the more common T version increased the odds of autism by 1.19 times.

(23andMe customers can check their data using the Browse Raw Data feature.)

Analysis of human fetal brain tissue revealed that the CDH10 gene is expressed at high levels in the frontal cortex, a brain region critical for language, social behavior and complex thought processes.

“It’s no coincidence that a gene linked to autism has a higher concentration in key brain regions that regulate speech and the ability to interpret social interaction. Our research suggests that CDH10 is switched on at a very early stage and plays an important role in regulating the developing brain.  This prenatal activity somehow makes the infant more susceptible to autism,” said Daniel Geschwind, a study co-author and director the UCLA Center for Autism Treatment and Research, in a statement.

In the second Nature study, also led by Hakonarson, researchers turned their focus away from SNPs — single letter differences in the genetic code — and instead investigated the role of copy number variations (CNVs) — small deletions and duplications DNA — in autism.

The CNVs Hakonarson and co-workers identified occurred mostly in genes that fall into two biological pathways: cell adhesion, the same pathway affected by the SNPs found in the first study, and the ubiquitin degradation pathway, a kind of cellular waste disposal system.  Among other things, enzymes in the ubiquitin pathway are involved in eliminating connections between nerve cells by destroying cell adhesion proteins, suggesting that variants in this pathway might also be affecting cell-to-cell connections in the brain.

In addition to their genetic findings, the authors say that recent neuroimaging studies that have suggested underconnectivity in the brains of subjects with ASDs and neuroanatomy studies that have implicated abnormal brain development in the frontal lobes of people with autism support the idea that altered cell-to-cell connections are a key component of autism.

Hakonarson and colleagues plan to continue researching autism, focusing their efforts on elucidating how the genetic variations they have identified might cause autism.  One experiment suggested by Hakonarson is to mutate cell adhesion proteins like cadherins in mice and look for changes in social behavior that mimic those seen in humans with autism.

Note:
A much smaller study, appearing online today in Molecular Psychiatry, found another genetic variant associated with autism.  Each copy of the A version of rs2217262 in the DOCK4 gene increased the odds of autism by 2.28 times.  Note that almost 90% of people with European ancestry have two copies of the A version of this SNP, meaning that these results really mean that the rare C version of the SNP is protective against autism. The authors of the study say that DOCK4 is involved in the extensions of brain cells that form synapses, the connections between brain cells.

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Experts estimate that 5% of the United States population — at least 15 million people — have weak spots in the arteries of their brains known as aneurysms. Each year about 27,000 of these bulging arteries burst, releasing blood into the space around the brain and potentially leading to stroke, brain damage or death.

The siblings of people who have had a ruptured brain aneurysm are four times more likely to suffer the same fate, suggesting that genes play a part in determining risk. So far, however, studies of families with a history of brain aneurysm and genes thought to be likely candidates have failed to produce any convincing genetic links.

A new study published online yesterday in Nature Genetics reports three genetic variants that, when combined, can increase the odds of brain aneurysm by almost three-fold. The variants increased risk independent of sex, family history and age.

Kaya Bilguvar and colleagues began by screening hundreds of thousands of SNPs in two European samples, one from Finland and one from the Netherlands. They then looked for evidence that the most strongly associated SNPs also increased the likelihood of aneurysm in a Japanese sample. All told, more than 2,100 people with brain aneurysm and 8,000 controls were studied. The authors say that they used a diverse population for their studies so that the results could be extended to a broader segment of the world’s population.

The researchers found associations between SNPs on chromosome 2, 8 and 9 (rs700651, rs10958409 and rs1333040, respectively) and brain aneurysm risk. A person with five or six “risky” copies (there are six possible – everyone has two copies of each of the three SNPs) has almost three times greater odds of having a brain aneurysm compared to someone who has zero or only one risky copy.

(23andMe customers can check their data for these SNPs using the Browse Raw data feature. A table with all of the relevant information is provided at the end of this post.)

SNPs in the same region of chromosome 9 as rs1333040 have previously been associated with arterial diseases, including brain aneurysm.

In many cases the first sign of a brain aneurysm is the catastrophic bleeding in the brain that happens when it ruptures. The authors of the current report caution that further work will be needed in this area and that there are most likely more DNA variants to be found. But they say their findings, in combination with assessment of other risk factors, could help identify people with brain aneurysms before it’s too late.

“Effect” is the increase in odds compared to someone with two copies of the non-risk version of each SNP as calculated in Bilguvar et al for the combined Finnish, Dutch and Japanese sample.

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