by Emily Chang and Chuong Do

This image shows the heritabilty of several diseases; the font size is proportional to the heritability of the disease. Celiac disease, for instance, is highly heritable, whereas lung cancer is much less heritable. Click on the chart to see a larger version. (Source: Chuong Do, unpublished manuscript)

What can you blame for those extra pounds, your great grandma Bertha’s obesity or that extra bowl of ice cream? “Nature” and “nurture” are commonly pitted against each other in discussions on genetics, but for most disease, both play a contributing role. In any population, individuals vary in their propensity for developing a given disease.  The proportion of this variation in the population that can be explained by genetics is known as “heritability.”

Heritability estimates vary considerably across common diseases.  For instance, celiac disease is highly heritable, meaning that the variability in the disease is mostly due to genetic differences. Other diseases are less heritable, such as lung cancer; the variability in this disease may be more correlated with non-genetic risk factors (e.g., smoking habits, diet, air pollution, etc.) than with genetic differences.

Heritability is a complex concept, and not surprisingly, is often misinterpreted. The most common misconception is that heritability describes the relative importance of genetics and environment for a specific individual. While useful at the population level, heritability actually doesn’t mean much at the individual level. For example, IQ is a highly heritable, but one can’t assume that a child born to parents of high IQ will also have a high IQ without factoring in the extremely important role played by his or her upbringing. As another example, breast cancer is estimated to have relatively low heritability (less than 33%), yet for a woman carrying a rare mutation in the BRCA1 or BRCA2 genes, knowledge of this single genetic factor will often have a substantially greater significance for her breast cancer risk than any known environmental factor.

Another misconception is the idea that a disease that is highly heritable must be determined by only a few genes that have a strong effect. Some diseases, such as cystic fibrosis, can be attributed solely to mutations in a single gene; this, however, is not always the case. The high heritability of schizophrenia, for example, is often believed to result from the contributions of many, many genes, each with small impact on disease risk.  A person could harbor lots of risk-predisposing variants for schizophrenia, yet still not have the disease.

Finally, many people assume that heritability for a given condition is constant across populations and over time.  In reality, heritability can be highly population dependent, and can change as the environment changes. For instance, height depends on both nutrition and genetics. In societies where nearly all children receive comparable nutrition, only genetic factors vary between individuals, so height appears highly heritable.  But in societies with greater economic disparities, height differences correlate more strongly with nutrition, resulting in lower heritability.

Although often misunderstood, heritability is a useful concept that can provide insights into the nature vs. debate.  More importantly, the low heritability of many diseases suggests that our collective disease destiny is only partially determined by our genes. You can’t change your DNA, but you can change your ice cream to frozen yogurt.

Heritability estimates from the scientific literature are typically based on twin studies and vary widely across diseases, as illustrated in the chart above.  Click on the chart to see a larger version. 
(Source: Chuong Do, unpublished manuscript).

According to the authors, the suicide of former star NFL linebacker Junior Seau, a death that mirrored other suicides of former NFL players who’d suffered degenerative brain damage, prompted them to provocatively ask whether prospective players of high impact sports or future soldiers should be genotyped to gauge their long-term risks from traumatic brain injuries.

Sam Gandy and Steven T. DeKosky point out that studies clearly link a person’s APOE-4 status — a genetic variant associated with higher risks for Alzheimer’s disease — with an increased risk for degenerative brain disease in response to traumatic brain injuries.

Would you want to know if your son or daughter had a higher risk?

I would. In fact, I do know because my kids have been tested.

What’s interesting is that Gandy and DeKosky asked about 100 traumatic brain injury experts whether they thought genotyping future athletes or soldiers was worthwhile. Most said it was too soon. But when asked whether they’d have their own children genotyped to gauge the risk, more than half said they would.

I thought that was telling.

It’s not just professional athletes and soldiers who are at risk from traumatic brain injury.
More than 1.7 million people a year sustain a traumatic brain injury and about 50,000 of them die each year, according the Center for Disease Control. There are both emotional and financial costs from these injuries.

It’s worth knowing more about the complicated environmental and genetic factors that could explain why traumatic brain injuries lead to long-term disabilities in some people and not in others.

Gandy and DeKosky’s paper is focused on APOE-4, traumatic brain injury and the risk of one form of degenerative brain disease.

23andMe is looking more broadly at this issue, studying the complicated interaction between our genetics and our environment. This can tell us a lot about health risks. It’s often said that our genetics “loads the gun, while the environment pulls the trigger.” In the case of traumatic brain injuries, there is increasing evidence of this interaction.

Recently we began genotyping professional boxers involved in a study being conducted by the Cleveland Clinic Lou Ruvo Center for Brain Health. This landmark study of professional fighters will help determine whether magnetic resonance imaging of the brain, along with other tests, can detect subtle changes in brain health that correlate with impaired thinking and functioning in response to boxing or head trauma. 23andMe is genotyping these athletes to help determine if there might be any genetic association that would make the athletes more or less susceptible to long-term injuries of the brain.

Our researchers are looking in other areas as well. 23andMe’s innovative research model allows us to track the relationship between certain genotypes and long-term disease. We’ve asked members of our Parkinson’s Research Community about their history of head trauma, for instance, and we have the ability to follow our community members over time, giving us insight into the connection between genetics, environmental factors and long term outcomes.

If the experts in traumatic brain injury think there’s value in using genotyping to gauge the risks of high impact sports for their own children, as noted by the authors in the Science paper, it must be of value to others too.

Although the majority of respondents to 23andMe’s Female Fertility survey stated that they weren’t trying to conceive the first time they became pregnant, around 13% said that they had tried or were currently trying to become pregnant, a percentage that’s on par with the national infertility average of 10-15%.

Infertility is defined as not being able to get pregnant after having frequent, unprotected sex for a year (or for six months if the woman is 35 or older). Although an infertility diagnosis can be frustrating, it doesn’t necessarily mean that you’ll never get pregnant — in many cases it just means that medical attention might be needed to secure a bambino!

Difficulties conceiving can stem from female or male problems (or both) and the causes vary, ranging from hormonal to structural, genetic, pharmacological or environmental. Other medical conditions including cancer and its treatment can also contribute to infertility and it’s been suggested that about 12% of cases are simply due to the woman being over or underweight. In about 20% of cases, however, the cause of the infertility is a mystery.

An important factor today is age since the chances of conceiving decrease 3-5% per year after the age of 30. This natural decline in fertility coupled with the fact that roughly one in five US women has her first child after the age of 35 means that one-third of “trying” older couples (with the woman over 35) experience fertility problems. It’s an interesting paradox: many women spend years gaining education and building their careers (and avoiding pregnancy) only to encounter difficulties when they actually want to conceive.

The Genetics Underlying Infertility

We know a bit about the genetics of male infertility and are starting to identify genetic factors for conditions that contribute to infertility in women, such as endometriosis, uterine fibroids and hypothyroidism. But overall the genetic factors underlying female fertility are not well understood and 23andMe aims to uncover part of that puzzle.

With this goal, 23andMe launched the Female Fertility survey and so far over 10,000 women have responded! With more data we should be able to find some genetic explanations for this complex condition, but for now we’d like to share some of the interesting characteristics of the initial survey responses.

Trying to Conceive Can be Quick or Take a While

• For their first child, 66% of 23andMe respondents conceived in the first 6 months of trying, 12% in months 7-12, 8% in months 13-24, and 8% after two years of trying. 5% of respondents tried without success and 2% were unsure of the timing.

Increasing the Odds of Conceiving

• 14% of respondents said that they underwent procedures or treatments the first time they tried to conceive. 52% took oral medicines to stimulate ovulation (like Clomid or letrozole), 8% used donor sperm, 28% underwent intrauterine insemination (IUI), and 19% did in vitro fertilization. (These categories are not mutually exclusive).

Roughly 25% Miscarry at Some Point

• It’s not always openly discussed, but a significant number of pregnancies end in miscarriage. 28% of respondents said they’d had at least one miscarriage, which is on par with some reports though slightly higher than the national average of about 15-20%. 90% of respondents miscarried in the first trimester, 13% in the second, and 2% in the third (1% were unsure). 52% were not evaluated for the cause of the miscarriage.

(These percentages are as of May, 2012 and will continue to change slightly over time as more women take the Female Fertility survey.)

Two of the biggest physical milestones in a woman’s life are menarche (pronounced “MEN-ar-kee”), the first menstrual period in girls, and menopause, when menstruation stops and female reproductive hormones slow. These milestones are universal and mark the beginning and end of a woman’s reproductive cycle.

Research suggests that the age at which menarche and menopause occur is about 50% influenced by genetics and 50% determined by non-genetic factors, though there is also some evidence that menarche may be more strongly influenced by genetics than menopause.

Age at Menarche
Studies have found that nearly all girls in the US menstruate by the age of 14, with the median age around 12 and one-half years. These numbers haven’t really changed over the last few decades, although girls today may show signs of puberty (breast growth and pubic hair display) at a younger age. The average age of menarche can vary by ethnicity, though, and African-American girls typically start menstruating before girls of European descent.

In addition to genetics, timing of menarche is influenced by environmental factors such as nutritional status and exercise. Early menarche has been associated with increased risk for breast cancer and endometrial cancer, a connection that many theorize is related to the body’s exposure to estrogen, a female reproductive hormone.

Age at Menopause
Menopause typically occurs between the ages of 40 and 60 with the average age around 51 years. A woman knows that she’s entering menopause if she experiences hot flashes, difficulty sleeping, irregular libido, and mood swings, symptoms that can sometimes be alleviated by hormone replacement therapy. A small fraction of women experience “early menopause” in their 30s, which can cause fertility problems and may also be influenced by genetic factors.

Research on Menarche and Menopause

Although some genome-wide association studies have been carried out to identify genetic factors for age at menarche, much less is known about the genetics underlying age at menopause. These important milestones are known to be influenced by ancestral origin, though more research is needed to identify genetic factors in non-European populations.

It’s National Women’s Health Week. Stay tuned for more posts about big health issues facing women today including autoimmune diseases, infertility and breast cancer.

Mother’s day marks the beginning of National Women’s Health Week. We’ll be running posts all week about universal female milestones (menarche and menopause) and a variety of other women’s health topics. Stay tuned!

Even looking specifically at breast cancer or sarcoma, the more researchers study these diseases, the more they understand that there are many different kinds of breast cancer and sarcoma.

This has been one of the most challenging aspects of researching cures for cancer.

This month is National Cancer Research Awareness Month, and 23andMe is highlighting our work in cancer research. We’re also talking to some of the people involved in the research and letting you know about some of the more exciting developments in the field.

Earlier this year, George Demetri, a doctor and scientist who is an unpaid advisor to our Sarcoma research initiative, noted how different sarcomas were. Not just under the microscope but when you look at them at the genetic level. Dr. Demetri said, this is where 23andMe’s research model offers so much promise. Using genetics may help us connect the right patient to the right drug. It can help change the one size fits all approach to clinical research and it holds the promise of other targeted medicines.

Scientists have found specific mutations that drive specific forms of cancer. There is already a long list of successes, Demetri said, whether from a drug that targets the HER2 protein in certain types of breast-cancer, or  from the use of Gleevec to target a specific protein in the treatment of chronic myeloid leukemia.
Right now, 23andMe has three studies focused on cancer.

We first applied our unique research platform to study cancer in April 2010 with the launch of our Sarcoma Research Initiative. We are already very close to reaching our goal of enrolling 1,000 people with the disease. Last summer we launched a Myeloproliferative Neoplasms Research Initiative to study this group of very rare blood cancers. More than 650 patients have joined this research project in just 9 months, and we announced our first research finding earlier this year. Finally, we’ve joined forces with Genentech to start a unique online breast cancer study to look at how genes influence a person’s response to treatment for metastatic breast cancer.

In each of these studies we believe we can change how clinical trials and cancer research is done. We want to make it cost less and take less time. We want to leverage the power of the web to bring down some of the barriers to participate and give people access to their genetic data in the process.

23andMe was started on this premise, and our research communities are the embodiment of that goal. Patients from all over the world can contribute directly to research and connect with others who have their disease, all while learning more about themselves.

We are also always looking for other genetic associations with cancer, and currently have two separate Cancer Family History Surveys, one for men and one for women.

We hope that over time this work will lead to important breakthroughs in the fight against cancer. Over the next few weeks we’ll be posting more stories about cancer, the research going on to fight the disease and some of the people at the forefront of that work. Stay tuned.

If you have a big head, you may be subjected to a fair bit of teasing, but science may offer you some consolation. For instance, individuals with a smaller intracranial volume (the area within the skull) are at slightly higher risk for late-life dementia. In addition, a smaller hippocampus (a section of the brain involved in learning and memory storage) has been associated with Alzheimer’s disease and mental illnesses such as depression and schizophrenia. Four papers published recently in Nature Genetics address various measures of head size and their possible health implications.

Factors influencing infant head circumference

An international team of scientists, led by H. Rob Taal from the Erasmus Medical Center in the Netherlands, has attempted to answer the question that has plagued numerous women in labor — why is my baby’s head so large?

Head size as an infant is highly heritable, meaning genetics accounts for a large portion of infant head circumference variability. To determine which genetic factors are involved, the team of researchers looked at genetic data from over 19,000 infants with European ancestry. They found that, on average, infants with the CC genotype at rs1042725 in the HMGA2 gene had heads that were approximately 1 mm larger around than infants with the CT genotype, and infants with the TT genotype had on average heads that were 1 mm smaller around. In addition, they found that each A at rs7980687 in SBNO1 gene was associated with approximately 1.2 mm larger head circumference.

Both of these SNPs are associated with height in adults. SBNO1, however, may play more of a role in neurological development; a similar gene found in fruit flies is related to development of a fly’s central nervous system.

Factors influencing intracranial volume

Early in life, brain volume and skull size are highly correlated. However, at a certain point the brain stops growing and begins to shrink while the skull remains the same size. Intracranial volume, which is the volume within the skull, is thus considered a good proxy for an individual’s maximum adult brain size.

Two of the recent Nature Genetics papers studied genetic factors influencing intracranial volume. A group of researchers led by Jason Stein from David Green School of Medicine at the University of California, Los Angeles, discovered that the SNP rs10784502 within the HMGA2 gene on chromosome 12 is associated with intracranial volume. The study, which used magnetic resonance imaging (MRI) to measure the skull size of over 15,000 individuals of European ancestry, suggests that the CC genotype at rs10784502 is associated with a 9.1 mL increase in intracranial volume over individuals with the CT genotype, and that the TT genotype was associated with a 9.1 mL decrease in intracranial volume.

Although the HMGA2 gene has been associated with height, this did not seem to fully account for the observed association between the SNP and intracranial volume. In a smaller, follow-up analysis the researchers also found that the C version of this SNP was associated with a very slight increase in IQ. But don’t “get a big head” about it if you happen to be CC at this SNP — the evidence was fairly weak and more research is needed to confirm these findings.

Another large team of researchers, led by M. Arfan Ikram, from the Erasmus Medical Center in the Netherlands, found two other SNPs influencing intracranial volume: rs4273712 on chromosome 6 and rs9303525 on chromosome 17. Each G at rs4273712 was associated with a 12.5 mL increase in intracranial volume, and each G at rs9303525 was associated with a 15 mL decrease in intracranial volume in a study of nearly 82,000 elderly individuals of European ancestry.

Factors influencing hippocampal volume

The hippocampus is a segment of the brain involved in learning and storing memories, and the size of the hippocampus has medical significance. A smaller hippocampal volume has been associated with depression, schizophrenia, and types of epilepsy. In addition, the hippocampus is often one of the first areas of the brain to be affected by Alzheimer’s disease, making it an early indicator of this disease.

A team of researchers led by Joshua C. Bis from the Department of Medicine at the University of Washington in Seattle looked at over 19,000 people with European ancestry and found that the C version at rs7294919 near the HRK-FBXW8 gene is associated with a 0.11 mL increase in hippocampal volume. Since the hippocampus shrinks as one ages, the authors equated this hippocampus size difference to a decrease of 3.9 years of age.

Curious about your brain genetics but not yet a customer? Join 23andMe today to learn more about your ancestry and health!

If your head is larger than most, be grateful for your possible lower risk of certain diseases and potentially higher IQ. But don’t let it go to your head — perhaps you should thank your parents for your big-head genes. Indeed, given the trouble your big noggin caused her, perhaps you should especially thank your mother this Mother’s Day!

Nature vs. nurture is a question scientists and non-scientists alike have grappled with since the earliest days of human history. One concept we use to describe these two complementary forces is “heritability”, or the proportion of variation in the development of a disease or trait in a population that’s due to genetics.

While this sounds simple, there are some nuances to heritability that often cause it to be misinterpreted. Show us what you know about heritability in this week’s quiz!

(Check back next week for the answers and to find out who won.)

A few of us from 23andMe attended the 6th Annual Conference for Women Living with Metastatic Breast Cancer two weekends ago in Philadelphia. This national conference is put on by a patient advocacy organization called Living Beyond Breast Cancer (LBBC) that empowers women affected by breast cancer to live longer, healthier lives.

The conference provided a toolbox of information for women fighting metastatic breast cancer — everything from treatment options to day-to-day coping to facing end-of-life issues. Metastatic breast cancer is a cancer that spreads from the breast to other parts of the body including the bones or liver.

It was an awe-inspiring event and we saw firsthand how brave, informed, and strong the metastatic breast cancer community is.

Continue reading for some conference highlights…

Patient and Physician Stories
The conference started with an inspiring testimonial by Pat Biedermann who has been fighting stage IV breast cancer for a number of years. She described how one of her first signs of metastasis was a cracking sound in her spine as she teed off on a golf course. Pat’s “tricks and tips” on living with the disease can be found on LBBC’s blog.

The next part of the conference featured a panel of physician-scientists that included Drs. Adam M. Brufsky, Julie R. Gralow, Harold A. Harvey, and Beth Overmoyer. They offered expertise on treatment options and gave an update on the latest in bench-to-bedside research on metastatic breast cancer.

The patient audience asked the panelists a variety of questions, for instance how do you decide when it’s time to a stop a treatment because of side effects? They also asked about genetic testing of tumors and expressed frustration over accessing clinical trials. (One individual said that finding a clinical trial that worked for her was like finding a needle in haystack.)

Clinical trials can be difficult for patients to access — the trial might be located far from where they live and the website that advertises them is largely geared towards physicians, containing technical language and eligibility criteria that can be hard to understand.

Personal Genetics and Drug Response
There was some discussion of the role of genetics in breast cancer. Although breast cancer can be strongly influenced by genetics — mutations in the BRCA genes are associated with a lifetime risk of about 50-60% — most cases are “sporadic”, meaning that the patient has no blood relative affected by the disease.

Breast cancer also comes in different forms and it’s becoming clear that it’s important to find out which kind you have because it can impact the course of treatment. For instance, many therapies aren’t effective in treating triple-negative breast cancer, which by definition is estrogen receptor-negative, progesterone receptor-negative, and HER2-negative. Since triple-negative cancers don’t display the receptors that most drugs target, it can be challenging to find a drug that will work for them.

The panelists also discussed how genetics can sometimes explain why some people respond well to a drug whereas others may experience serious side effects. This was of particular interest to 23andMe because we not only offer our customers reports on how their genetics might influence responses to different drugs but also perform research to understand these genetic responses. Our research into this area includes antidepressants, commonly used medications, and now bevacizumab in breast cancer as part of the InVite study (see sidebar).

Looking Ahead
Living beyond breast cancer pretty much sums up the goal of the conference attended by 23andMe employees including InVite Project Lead Dr. Kimberly Barnholt. “It was inspiring to meet such knowledgeable and empowered women at the LBBC conference,” she said. “We are excited to partner with this community of active and passionate individuals to explore innovative approaches to research that will hopefully lead to better treatments and maybe even an eventual cure for breast cancer.”

Which physical trait is most associated with BMI? Shoe size.

Shoe size is very strongly correlated with BMI in 23andMe’s database. For each standard deviation increase in shoe size, BMI increases by 1.18 units. Put another way, the BMI of the bottom fifth of the shoe size distribution is 3.21 units lower on average than that of the top fifth. This corresponds to a difference of about 20 lbs in people who are 5’8” tall.

We’re really not sure what to make out of this one. Shoe size is also correlated with height but when we factored height into the analysis shoe size was still the most strongly correlated trait. Anecdotally, people’s shoe sizes can increase or decrease with weight gain and loss. It’s possible that people with wider feet may compensate by increasing their shoe size instead of choosing a wider shoe of the same size, or perhaps shoe size is a proxy for body frame, and people with larger shoe sizes have “bigger bones”. Have a theory? Add it to the comments below.

Having a round face, low arches, upturned nose, and feet that point outwards are also associated with BMI but to a lesser extent.

Which food item is most associated with BMI? Diet soda.

The surprise for us here was that ice cream consumption was not really correlated with BMI at all. On the other hand, people who drink diet soda five or more times a day have an average BMI nearly 5 units higher than those who never drink diet soda. Not to imply that we should all trade in that diet coke for a double hot fudge sundae — we don’t know whether drinking soda is a cause, a consequence, or just linked to something else that causes weight gain. These findings do, however, parallel that of a study conducted in Texas, in which normal weight individuals were followed for 8 years. People who reported drinking more diet soda gained more weight over those 8 years, suggesting that diet soda might actually lead more directly to weight gain.(1) But for now, the jury’s still out.

Some other foods were associated with BMI, too, including red meat, yogurt, and vegetables.

Which personality or behavior trait is most associated with BMI? Activity and depression.

These are less of a surprise. Activity is strongly correlated with BMI, and is no doubt due to the calorie burning benefits of exercise. The reverse may also be true — being overweight may itself decrease activity levels, creating a vicious cycle.

For depression, the arrow of causation seems to point in both directions. For example, a recent meta-analysis found that being overweight or obese increased the risk of developing depression, and having depression increased the risk of becoming obese.(2)

Having greater levels of self-discipline was correlated with lower BMI to a lesser extent, but aside from this we didn’t find a significant relationship between BMI and any other personality factors.

Check back soon for our next quiz and another chance to win!

(1) Fowler, SP, Williams, K, Resendez, RG, Hunt, KJ, Hazuda, HP, & Stern, MP. (2008). Fueling the Obesity Epidemic? Artificially Sweetened Beverage Use and Long-term Weight Gain. Epidemiology, 16(8): 1894-1900.

(2) Luppino, FS, de Wit, LM, Bouvy, PF, Stijnen, T, Cuijpers, P, Penninx, BWJH, Zitman, FG (2010). Overweight, Obesity, and Depression: A systematic review and meta-analysis of longitudinal studies. Arch Gen Psychiatry. 2010;67(3):220-229.