Our bones are amazing structures, capable of supporting tremendous force through complex motions. They do this day in and day out, year after year as we sit, stand, walk, run, lift, work, and play. But as the elderly among us know all too well, bones are not invincible and become more fragile as we age. As the natural, continuous cycle of bone turnover slows down and becomes unbalanced, bone is broken down faster than it is replaced — and important bone-strengthening minerals like calcium are lost.

Low bone mineral density (BMD) is one of the hallmarks of osteoporosis (literally “porous bones”), a disease that impacts nearly 45 million people in US and is responsible for more than one million fractures each year. Women develop osteoporosis much more frequently than men, especially after menopause. The burden on the health care system is significant and is expected to double over the next 10-15 years as the population ages.

Although it is natural to lose bone mass as we get older, genetic factors are known to play a large role in determining bone mass and the rate at which bone mineral density decreases. The relationship between genetics and BMD is complex, and association studies have implicated many different genes that may play a role. New research published this week in Nature Genetics continues the search for genetic factors and has identified more than a dozen SNPs associated with BMD in Europeans.

The team of researchers, led by Fernando Rivadeneira and Andre Uitterlinden of the Erasmus Medical Center in The Netherlands, used data from the Genetic Factors for Osteoporosis (GEFOS) Consortium containing lumbar spine BMD and femoral neck BMD measurements for almost 20,000 individuals. About half of the variants they identified replicated previously reported genetic associations with BMD, but the other half were new.

Some of the SNPs were associated with lower BMD while others were associated with higher BMD. For instance, individuals with one or more copies of the C allele at rs1366594 tended to have lower lumbar spine BMD than those without, and individuals with one or more copies of the C allele at rs2566755 tended to have higher lumbar and femoral neck BMD.

(23andMe customers can see their data for the SNPs currently covered by 23andMe’s service using the Browse Raw Data feature. See the table at the end of this post.)

The exact biological processes affected by these variants are still unclear, but increasing evidence points to several signaling pathways known to be important in bone biology.

One of these pathways is mediated by the “Wnt” family of proteins; Wnt signaling is important both for proper differentiation of cells responsible for breaking down bone and for the development of cartilage, required for new bone formation. rs87939, for instance, is near the gene that encodes β-catenin, an important node through which Wnt proteins influence cellular processes such as gene expression (this SNP is not on 23andMe’s platform but correlates perfectly with one that is, rs450615). Wnt proteins can also act through other channels potentially affected by additional SNPs identified by this study.

Another pathway implicated by the growing body of research is estrogen signaling. There is no doubt that the drop in estrogen following menopause in women leads to increased risk for osteoporosis, and hormone replacement therapy can have a protective effect. Not surprisingly, estrogen affects numerous biological processes – including bone maintenance – mainly through its role in gene expression. Variants in ESR1, the major estrogen receptor found in bone, have been associated with BMD and osteoporosis, though results are far from conclusive. Rivadeneira and colleagues confirmed the association of a SNP in ESR1, rs2504063, with lumbar spine BMD. Several other SNPs are also located in or near genes that may influence the regulation of bone development.

Osteoporosis is the most common bone disorder in developed countries. One in two women and one in four men over the age of 50 will experience a bone fracture due to the disease. Diets rich in calcium (especially before your mid-30s) and regular exercise can help combat bone loss. Meanwhile, the search carries on for clues that could lead to greater understanding of bone disease and potential avenues for treatment.

SNPs associated with bone mineral density (BMD):

* In some cases, 23andMe does not cover the original SNP, so a proxy SNP that correlates perfectly with the original in Europeans is reported instead.

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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No matter when it happens, puberty is no fun.  But for girls, entering womanhood earlier or later than average can mean more than just the social awkwardness of being quick to mature or a late bloomer.  It can have important health consequences later in life.

In general, girls in the developed world are maturing faster now than ever before.  In the mid-nineteenth century the age at menarche (the first menstrual period, a milestone usually reached about two to three years after puberty begins) was about 16, but by the end of the twentieth century that number had fallen to about 13. Earlier age at menarche has been associated with an increased risk for breast, ovarian and endometrial cancer. On the other hand, later menarche is linked to increased risk for osteoporosis and cardiovascular disease.

Much of the change in the rate of maturation for girls has been attributed to better nutrition and rising rates of obesity, but new research shows that the age at menarche is also influenced by genetics.

Four papers (Ong et al., Sulem et al., Perry et al., and He et al.), published online yesterday in the journal Nature Genetics, analyzed data from a total of more than 60,000 women with European ancestry and identified two regions of the genome that contain variations associated with small differences in age at menarche.  One of these four studies, and a fifth paper (Stolk et al.), also found variations associated with the timing of menopause, the other end of the reproductive spectrum for women.

All four studies looking at age of menarche found a connection with a region of chromosome 6. Each paper identified slightly different variants, but they all appear to be zeroing in on a single, yet to be found, causative variation in the DNA.  As an example of the effect of the chromosome 6 SNPs, Ong et al. found that compared to those with two Cs, each T at rs314263 meant that woman got her first period about six weeks earlier.

(Ong et al. actually looked at rs314276, but we’re focusing on rs314263, a perfect proxy for the original SNP.  23andMe customers can check their data for rs314263 using the Browse Raw Data feature.)

Each T at rs314263 was also associated with 1.20 times greater odds of breast development at age 10, 1.26 times greater odds of advanced breast development between the ages of 9 and 16 and a faster rate of increase in height and weight.

Although girls who go through puberty earlier than their peers are tall for their age during childhood, their growth stops sooner and they are generally shorter as adults.  Ong et al. found that each T at rs314263 was associated with a reduction in adult height of about 0.15 inches.

Two studies also found an association between variations on chromosome 9 with age at menarche.  Each C at rs7861820 (the most significant SNP found in He et al.), for example, translated into about five weeks earlier menarche.

He et al. and Stolk et al. found variations in five regions of the genome associated with another big change in a woman’s life: menopause. The risks associated with the timing of menopause are the reverse of those associated with menarche: later menopause has been associated with higher risk for certain cancers and earlier menopause is linked to increased risk for osteoporosis and cardiovascular disease.

(23andMe customers can check their data for SNPs representative of these five regions using the table at the end of this post.)

Finally, all of you boys and men out there need not feel left out:  Ong et al. also looked at the effects of rs314263 on puberty in males.  They found that each copy of an T translated into 1.26 greater odds of advanced voice breaking at age 15, 1.19 times greater odds of advanced pubic hair at age 13, faster rate of growth at age 10 and about a tenth of an inch less in adult height.

SNPs Associated With Menopause

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Melanoma, a rare but potentially deadly form of skin cancer, is more common in women under 40 than in men in the same age group.  After age 45, the tables are turned: men are more likely to be diagnosed with melanoma.

Between the ages of 40 and 50 happens to be when many women enter menopause or perimenopause, a time of declining estrogen levels.  This has prompted some researchers to suggest that estrogen exposure may play a part in melanoma risk.

In a report published last week in Clinical Cancer Research, researchers show that a genetic variation previously associated with several other cancers may be the link between estrogen and melanoma in younger women.  The riskier version of the variation increases the odds a woman will be diagnosed with melanoma before age 40 more than fourfold.

“Potentially, we have a genetic test that might identify pre-menopausal women who are at higher risk for melanoma.  And if that’s the case, then we might want to have increased surveillance of those patients including more frequent visits to the doctor, more rigorous teaching of skin self-examination, and other preventive steps,” said Dr. David Polsky, the study’s lead author, in a statement.

In a sample of 227 people with melanoma – 93 women and 134 men – researchers found that women with two Gs at SNP rs2279744 were diagnosed with the disease 13 years earlier than those with GT or TT at this SNP.  In men, there was no effect of rs2279744 on age at diagnosis.

About 52% of women with GG at this SNP were diagnosed with melanoma before age 50 – and 38% between ages 30 and 39.  Only about 22% of women with GT or TT were diagnosed before age 50. Although those figures are dramatic, it is important to remember that the SNP was not shown to affect melanoma risk generally, but the age at which people who do develop it are diagnosed.

(23andMe customers can check their data for rs2279744 using the Browse Raw Data feature.)

SNP rs2279744 is in a gene called MDM2.  Laboratory experiments have shown that the G version of this SNP causes the MDM2 gene to be turned on at higher levels in response to estrogen than the T version.

Higher levels of MDM2 protein may be relevant to melanoma, as well as other cancers, because its role in cells is to regulate a tumor suppressor protein called p53.  More MDM2 means less p53, which in turn can reduce a cell’s protection against turning into a cancer cell.

More research will be needed to confirm that there is an interaction between estrogen and the G version of SNP rs2279744 that affects melanoma risk.  The authors caution that their study was small, lacked information about the menopausal status of the women they studied and did not include a group of people without melanoma for comparison.

More work will also be needed to understand how the MDM2 gene and the protein it encodes affect cancer risk in general.  The G version of SNP rs2279744 has been associated with earlier onset for some cancers, including soft tissue sarcoma, diffuse large B-cell lymphoma, colorectal cancer, ovarian cancer and non-small cell lung cancer in women, and decreased survival in people with stomach and kidney cancer.  But there is evidence for improved survival in women with ovarian cancer who have the G version of this SNP.  Paradoxically, higher levels of the MDM2 protein (as would be expected with the G version of SNP rs2279744 shown to lead to earlier melanoma onset in the current study) have been associated with improved survival for melanoma.

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