Can a Tendency to Sit Be Inherited ?

by | Sep 15, 2020 | Genetic or Environmental?

Main Takeaways:

  • Sedentary behavior (sitting or lying down for long periods of time) is harmful to your health, increasing your risk for cardiovascular disease, cancer, type 2 diabetes, and other health issues.
  • While the tendency to engage in sedentary behavior appears to be somewhat heritable, it is largely influenced by your environment. This means even if you have a genetic tendency toward sedentary behavior, you aren’t destined to engage in high levels of sedentary behavior; everyone can make small changes to their routine and environment to lessen time spent sitting.
  • More inclusive research in this area is needed, as well as more standardized definitions of sedentary behaviors and measures

How much time do you spend sitting each day? You have probably heard recommendations from health organizations about how much exercise you should get, how many steps you should take, or how much time you should spend looking at digital screens. However, not much is said about your sedentary behavior, or how much time you spend sitting or lying down. Sedentary behavior, which requires very little energy expenditure, is a distinct behavior from physical activity [1] . Physical activity is usually thought of as exercise; for example, you would be meeting physical activity recommendations if you ran for 30 minutes each day. Yet, even if you meet this recommendation, there is still ample opportunity to engage in sedentary behavior. Let’s say you spend an hour total commuting to and from work, sit at your office job for 8 hours, work out at the gym for 30 minutes after work, then come home and watch TV for the rest of the night until bedtime. With that routine, you would be considered physically active while still spending the majority of your waking hours sitting. How does all of this inactivity affect your health?

Sedentary behavior (SB) has repeatedly been linked to negative health impacts. A study by P. T. Katzmarzyk et al. [2] found that greater sitting time is associated with higher all-cause mortality as well as cardiovascular disease. These associations remained even in individuals that were considered physically active. In addition, a meta-analysis found positive associations between SB and cancer, type 2 diabetes, cardiovascular disease, and all-cause mortality [3]. SB has also been linked to shorter telomeres [4], organ damage, neck, shoulder, and back pain, muscle degeneration, poor circulation, and damage to discs in the spine [5].

So who is most likely to be affected by SB, and therefore more likely to suffer from these health impacts? Can you be genetically predisposed to sit more? Over the past 10 years, 8 studies have explored the heritability of SB using heritability estimates. These estimates help us to gauge a trait’s heritability; they suggest the percentage of phenotypic variability that is influenced by genetics within a population. The higher the estimate, the more influence genetics is thought to have on the trait. Heritability estimates for SB range from 7% to 56%, with an average estimate of 26% [8-15]. Twin studies were the most common form of study performed, finding heritability estimates ranging from 26%-56% [8, 13, 14, 15]. Family studies found heritability estimates ranging from 7%-41% [9, 11, 12], and the only genome-wide association study (GWAS) reported estimates of 15% (men) and 18% (women) [10].

This GWAS also discovered four loci associated with SB, near genes MEF2C, EFNA5, LOC105377146, and CALN1 [10]. These genes are related to muscle maintenance, nervous system development, and calcium binding [16-19]. Other possible candidate genes mentioned by these studies but not evaluated directly include DRD1, NHLH2, and MC4R [8]. DRD1 is related to dopamine responses and is thought to be involved with some behavioral responses, which could affect reward systems involved with activity [20]. The effect of NHLH2 on SB is less clear but seems to be related to the process of transcription [21], while MC4R produces a melanocortin hormone and is known to be a cause of monogenic obesity [22]. Each of these genes can be plausibly connected to SB; your muscles, nervous system, reward pathways, and more could all be involved in the regulation of this behavior.

Does this mean you are doomed to a sedentary lifestyle and the resulting negative health consequences if you possess variants in these genes? Luckily, that does not appear to be the case. Each of these studies promoted the idea that environmental factors have a larger influence on SB than genetics alone. This means even if you had a genetic tendency toward sedentary behavior, you wouldn’t be destined to engage in high levels of sedentary behavior; everyone can make small changes to their routine and environment to lessen time spent sitting and diminish SB’s harmful effects of the body [6]. I am currently working with Dori Rosenberg’s research team at the Kaiser Permanente Washington Health Research Institute, supporting an intervention that helps older adults make small changes in their daily lives with the goal of reducing their sitting time. By making participants more aware of how much they sit in addition to providing tools and coaching to help them sit less, this study hopes to see a decrease in SB among participants receiving the intervention. Suggestions for sitting less from the Office of Disease Prevention and Health Promotion include walking or riding a bike to get to work instead of driving, taking regular standing breaks (every 20-30 minutes) from sitting throughout the workday or while watching television, and pacing while talking on the phone instead of sitting[7] . So while studies did identify SB as a heritable trait and there are some candidate genes thought to be associated with SB [8,10], this behavior is largely affected by your environment and daily decisions. You have control over your SB regardless of your genetics.

I would be remiss, however, without describing some of the issues within existing genetic SB research. It is well known that people of non-European ancestries are continually excluded from genetic research, and a large portion of this research focuses on samples drawn from populations of European descent [23]. Six out of the eight studies I reviewed used samples of predominantly European descent [8, 9, 10, 13, 14, 15] , while the two remaining studies focused on Brazilian [11] and Portuguese [12] populations. None of the studies included representative samples of people with African, Asian, or Indigenous descent. It is important to include populations of diverse ancestries in order to increase the chances of discovering variants associated with a trait of interest, better understand the frequencies of a variant of interest in different populations, have more accurate representation of the diversity in humans [11] , and to make research more inclusive.

A second recurring limitation in the literature was the measurement of SB. The studies reviewed provided evidence that different results are seen when data are procured by self-report rather than an objective measure such as a wearable activity monitor. Downfalls of self-report are well documented [24], as this method can result in social desirability bias, recency bias, and a simple inability to accurately remember or estimate their SB. It is possible that studies using objective measurement methods may find higher heritability estimates on average — studies that used objective measurement found an average heritability estimate of 30% compared to 25% in studies that used self-report, though this comparison is based on just a few studies. For these reasons, future research should prioritize objective measurement for more accurate results. In addition, not all studies evaluated SB in the same way even within the categories of self-report and objective measurement. The lack of clear definitions and standard measures complicate comparison between studies, weakening what conclusions can be gleaned from the literature.

Despite these limitations, current evidence suggests that SB is heritable. However, it is also highly modifiable. Even if linkages between increased SB and certain gene variants were identified, knowing your genotype is unlikely to help you reduce your sitting time. This is good news — you can start making changes today to work toward sitting less, improving your overall health, and reducing your risk of chronic diseases. What are you waiting for?

References

  1. Sedentary Behavior Research Network. (2019, September 5). SBRN Terminology Consensus Project. Retrieved from https://www.sedentarybehaviour.org/sbrn-terminology-consensus-project/
  2. Katzmarzyk, P. T., Church, T. S., Craig, C. L., & Bouchard, C. (2009). Sitting Time and Mortality from All Causes, Cardiovascular Disease, and Cancer. Medicine & Science in Sports & Exercise, 41(5), 998–1005. https://doi.org/10.1249/mss.0b013e3181930355
  3. Biswas, A., Oh, P. I., Faulkner, G. E., Bajaj, R. R., Silver, M. A., Mitchell, M. S., & Alter, D. A. (2015). Sedentary Time and Its Association With Risk for Disease Incidence, Mortality, and Hospitalization in Adults. Annals of Internal Medicine, 162(2), 123. https://doi.org/10.7326/m14-1651
  4. Sjögren, P., Fisher, R., Kallings, L., Svenson, U., Roos, G., & Hellénius, M.-L. (2014). Stand up for health—avoiding sedentary behaviour might lengthen your telomeres: secondary outcomes from a physical activity RCT in older people. British Journal of Sports Medicine, 48(19), 1407–1409. https://doi.org/10.1136/bjsports-2013-093342
  5. Berkowitz, B., & Clark, P. (2014, January 20). The Health Hazards of Sitting. Retrieved from https://www.washingtonpost.com/gdpr-consent/?next_url=https%3a%2f%2fwww.washingtonpost.com%2fapps%2fg%2fpage%2fnational%2fthe-health-hazards-of-sitting%2f750%2f%3fitid%3dlk_inline_manual_8&itid=lk_inline_manual_8
  6. Barwais, F. A., Cuddihy, T. F., & Tomson, L. (2013). Physical activity, sedentary behavior and total wellness changes among sedentary adults: a 4-week randomized controlled trial. Health and Quality of Life Outcomes, 11(1), 183. https://doi.org/10.1186/1477-7525-11-183
  7. National Center on Health, Physical Activity and Disability. (2013, January 30). Decreasing Sedentary Behavior and Physical Inactivity by Moving More and Sitting Less. Retrieved from https://health.gov/news-archive/blog/2013/01/decreasing-sedentary-behavior-and-physical-inactivity-by-moving-more-and-sitting-less/
  8. den Hoed, M., Brage, S., Zhao, J. H., Westgate, K., Nessa, A., Ekelund, U., … Loos, R. J. F. (2013). Heritability of objectively assessed daily physical activity and sedentary behavior. The American Journal of Clinical Nutrition, 98(5), 1317–1325. https://doi.org/10.3945/ajcn.113.069849
  9. Diego, V. P., de Chaves, R. N., Blangero, J., de Souza, M. C., Santos, D., Gomes, T. N., … Maia, J. A. R. (2015). Sex-specific genetic effects in physical activity: results from a quantitative genetic analysis. BMC Medical Genetics, 16(1), 1. https://doi.org/10.1186/s12881-015-0207-9
  10. Doherty, A., Smith-Byrne, K., Ferreira, T., Holmes, M. V., Holmes, C., Pulit, S. L., & Lindgren, C. M. (2018). GWAS identifies 14 loci for device-measured physical activity and sleep duration. Nature Communications, 9(1), 1. https://doi.org/10.1038/s41467-018-07743-4
  11. Leite, J. M. R. S., Soler, J. M. P., Horimoto, A. R. V. R., Alvim, R. O., & Pereira, A. C. (2019). Heritability and Sex-Specific Genetic Effects of Self-Reported Physical Activity in a Brazilian Highly Admixed Population. Human Heredity, 84(3), 151–158. https://doi.org/10.1159/000506007
  12. Santos, D. M. V., Katzmarzyk, P. T., Diego, V. P., Blangero, J., Souza, M. C., Freitas, D. L., … Maia, J. A. R. (2014). Genotype by Sex and Genotype by Age Interactions with Sedentary Behavior: The Portuguese Healthy Family Study. PLoS ONE, 9(10), e110025. https://doi.org/10.1371/journal.pone.0110025
  13. Schutte, N. M., Huppertz, C., Doornweerd, S., Bartels, M., Geus, E. J. C., & Ploeg, H. P. (2020). Heritability of objectively assessed and self‐reported sedentary behavior. Scandinavian Journal of Medicine & Science in Sports, 30(7), 1237–1247. https://doi.org/10.1111/sms.13658
  14. van der Aa, N., Bartels, M., te Velde, S. J., Boomsma, D. I., de Geus, E. J. C., & Brug, J. (2012). Genetic and Environmental Influences on Individual Differences in Sedentary Behavior During Adolescence. Archives of Pediatrics & Adolescent Medicine, 166(6), 509. https://doi.org/10.1001/archpediatrics.2011.1658
  15. Waller, K., Vähä-Ypyä, H., Lindgren, N., Kaprio, J., Sievänen, H., & Kujala, U. M. (2018). Self-reported Fitness and Objectively Measured Physical Activity Profile Among Older Adults: A Twin Study. The Journals of Gerontology: Series A, 74(12), 1965–1972. https://doi.org/10.1093/gerona/gly263
  16. (2020a, June 1). LOC105377146 uncharacterized LOC105377146 [Homo sapiens (human)] Retrieved from https://www.ncbi.nlm.nih.gov/gene/?term=loc105377146
  17. NCBI. (2020c, June 7). CALN1 calneuron 1 [Homo sapiens (human)]. Retrieved from https://www.ncbi.nlm.nih.gov/gene/83698
  18. NCBI.(2020d, June 7). EFNA5 ephrin A5 [Homo sapiens (human)]. Retrieved from https://www.ncbi.nlm.nih.gov/gene/1946
  19. NCBI. (2020g, June 28). MEF2C myocyte enhancer factor 2C [Homo sapiens (human)]. Retrieved from https://www.ncbi.nlm.nih.gov/gene/4208
  20. NCBI.(2020b, June 4). DRD1 dopamine receptor D1 [Homo sapiens (human)]. Retrieved from https://www.ncbi.nlm.nih.gov/gene/1812
  21. NCBI. (2020e, June 7). NHLH2 nescient helix-loop-helix 2 [Homo sapiens (human)]. Retrieved from https://www.ncbi.nlm.nih.gov/gene/4808
  22. NCBI. (2020f, June 27). MC4R melanocortin 4 receptor [Homo sapiens (human)]. Retrieved from https://www.ncbi.nlm.nih.gov/gene/4160
  23. Genetics for all. (2019). Nature Genetics, 51(4), 579. https://doi.org/10.1038/s41588-019-0394-y
  24. Rosenman, R., Tennekoon, V., & Hill, L. G. (2011). Measuring bias in self-reported data. International Journal of Behavioural and Healthcare Research, 2(4), 320. https://doi.org/10.1504/ijbhr.2011.043414
What You Should Know about the Genetics of Alzheimer’s before Ordering an At-home Genetic Test

What You Should Know about the Genetics of Alzheimer’s before Ordering an At-home Genetic Test

by | Jun 1, 2020 | Disease Genetics, Genetic Misconceptions

Main Takeaways:

  • Late-onset Alzheimer’s Disease (LOAD) is influenced by many genetic and environmental risk factors. There is no gene that guarantees onset or immunity from (LOAD).
  • At-home genetic testing companies that offer an “Alzheimer’s test” are only testing one variant from one gene (APOE). The presence or absence of this APOEε4 variant is not a diagnosis.
  • Thus far, over two dozen risk loci for LOAD have been discovered, yet a genetic test is not sufficient to detect one’s true risk of developing disease.

When I was seven years old, my parents took me back to their hometown of Shanghai to visit my grandparents. It was a long trip we had taken before, and while the 18-hour journey was tiring, I was looking forward to seeing family, eating street food, and finding cats in the park. This trip was different, however. My mom explained to me that my grandpa may not remember us. He has Alzheimer’s, she said. Although I didn’t know what that meant, it made sense to me that my grandpa may not remember me. After all, I had changed a lot between three and seven. When we finally arrived at my grandparents’ home, I realized that it wasn’t that my grandpa was forgetful; there was a blankness. He couldn’t leave his bed.

My grandpa was suffering from a neurodegenerative disease – meaning it affects the brain and becomes worse over time. Alzheimer’s disease is the most common cause of dementia, affecting an estimated 5.8 million people in the United States and 1 out of every 10 people over age 65 [1]. The disease is devastating for those affected, their caregivers, and their loved ones. When 23andMe and other at-home (direct-to-consumer) genetic testing companies began testing for Alzheimer’s disease risk, I understood the impulse to spit in a tube and find out one’s genetic risk for the disease [2]. That impulse is driven by the feeling of fear that immediately follows annoyance when my mom turns the car back around two minutes after leaving the house because she can’t remember if she left the stove on. Of course, I want to know my risk for disease and everything I can do to prevent it. The fact is, that’s just not possible yet.

That impulse to order the genetic test is also based on the misconception that all of the genetic causes of Alzheimer’s disease are known. Last year Cosmopolitan published an op-ed titled “I tested positive for the Alzheimer’s Gene at 26 years old,” where the author shared her emotional experiences after receiving her genetic testing results and the lifestyle changes she made to help prevent the disease [3]. While I don’t believe genetic testing companies are trying to be scientifically deceiving, the op-ed highlights the consequences and unwarranted anxiety that can occur when the science and genetics of Alzheimer’s disease are not clearly presented. In this post, I will share the facts about Alzheimer’s Disease genetics. (For the rest of this post, Alzheimer’s Disease will be referred to as AD).

There are two classifications of AD: early-onset AD and late-onset AD. Early-onset AD is rare. It accounts for about 1% of all AD cases [4]. Unlike most AD cases, the genetic causes of early-onset AD are known; it is caused by mutations in the genes APP, PSEN1, or PSEN2. Early-onset AD is transmitted in a dominant Mendelian pattern. For every gene, you receive one copy (allele) from your father and one from your mother. A dominant Mendelian pattern means that if you receive just one copy with a mutation, you will develop the disease. Once again, I want to reiterate that this type of AD is very rare. If you have a family history of early-onset AD and are not in contact with a medical provider or research group, you can find more information and resources here [5].

The more common version of AD, the type that my grandpa had and the version most direct-to-consumer genetic testing companies offer a test for, is late-onset AD. Unlike the early-onset version, late-onset AD is a complex, genetically heterogeneous trait, meaning it is influenced by both environmental and genetic factors. Furthermore, different genetic variants cause the disease in different people. In other words, there is no “Alzheimer’s gene.” There are many variants in many genes that add to one’s genetic risk, and many risk variants have not been discovered yet.

So why the hype? What is the scientific basis for the direct-to-consumer late-onset AD tests that have resulted in online forums, Facebook support groups, and op-eds in popular magazines?

The direct-to-consumer tests calculate genetic risk based on the variation in a single gene: APOE. Everyone has the APOE gene on chromosome 19; what matters for AD risk is which variants of the gene you have [6]. There are three variants (six possible combinations): ε2, ε3, and ε4. APOE ε2 has been found to have protective effects, while APOE ε4 is the variant associated with an increased risk of late-onset AD. Studies have found that on average, having one copy of ε4 increases the risk for late-onset AD by 3-fold, and having two APOE ε4 alleles increases risk by 12-fold [4].

I am not trying to dismiss concerns over this increased risk; three times higher and twelve times higher risk are significant. APOE ε4 is the strongest genetic risk factor for late-onset AD that we know of. However, it is important to keep the following in mind:

(1) Inheriting two copies of APOE ε4 is rare, affecting only 2-3% of the population (see image below) [4].

(2) Late-onset AD is influenced by genetic risk factors AND environmental factors, with one study showing that 47% of the variance of AD is due to non-genetic factors [7].

(3) Having two copies of APOE ε4 is not an Alzheimer’s disease diagnosis, nor is the absence of APOE ε4 a guarantee that you will not get AD. Environmental factors aside, there are many other genetic variants that confer risk for late-onset AD (see image below).

(4) Finally, the overwhelming majority (over 90%) of research on the genetic risks of Alzheimer’s have been conducted in samples of people of non-Hispanic European descent [8]. The few studies of APOE risk on AD in diverse populations have shown that the risk of AD caused by the APOE ε4 allele varies depending on ancestry.  In 2019, a study of late-onset AD in Caribbean Hispanics found that individuals with African-derived ε4 allele at the APOE gene had 39% lower odds of having AD than those with a European-ancestry-derived copy of ε4 [9].

Image from Celeste M. Karch, and Alison M. Goate, “Alzheimer’s Disease Risk Genes and Mechanisms of Disease Pathogenesis.” Alzheimer’s risk-variants are plotted with frequency in the population on the X-axis and the risk conferred by each variant on the Y-axis. Mutations in PSEN1, PSEN2, and APP cause early-onset Alzheimer’s disease. Dozens of genetic mutations have been confirmed to increase risk of late-onset Alzheimer’s disease, with APOE ε4 being the strongest known disease-variant.

The bottom line is that these direct-to-consumer genetic tests of late-onset AD can tell you one piece about your risk for disease, but it can’t factor in how APOE interacts with other genes or with your environment; the test is based primarily on research of those with European ancestry; and it cannot tell you whether or not you will have Alzheimer’s disease. I look forward to the day when I can edit this post to say that an accurate assessment for late-onset AD genetic risk exists, but we’re not quite there yet. (note: if you are thinking about ordering an direct-to-consumer genetic test for AD, the Alzheimer’s Association strongly recommends you consult with a genetic counselor before the test and after receiving your results).

That trip in 2004 was the last time I saw my grandpa. At the time, I didn’t know what was happening, but I could feel the hopelessness in the air. It hits kids hard when the adults in the room are saying they don’t know anything more, that nothing can be done. I understand that it can seem discouraging that there is so much we still don’t know, that there is still no cure. But I am not hopeless anymore. In 2004, studies of the human genome were in its infancy, with The Human Genome Project having been completed only months before. At the time, there had been no genome-wide studies of Alzheimer’s disease. In the past 15 years alone, 40 genomic regions that are associated with late-onset AD have been found [10]. Every year, we learn more about new risk variants and biological pathways that can be targeted for pharmaceutical therapies. Significant efforts are being put toward researching the genetics of Alzheimer’s, worldwide, with the hope that one day we will understand the entire genetic architecture of the disease. I am optimistic for what the next 15 years will bring.

 

References:

[1] 2020 Alzheimer’s Disease Facts and Figures. Alzheimer’s Association. Retrieved from https://www.alz.org/media/Documents/alzheimers-facts-and-figures.pdf

[2] Late-onset Alzheimer’s Disease. 23andMe. Retrieved from https://www.23andme.com/topics/health-predispositions/late-onset-alzheimers/

[3] Brown, S. “I Tested Positive for the Alzheimer’s Gene at 26 years old.” Cosmopolitan Sep. 19, 2019. Retrieved from https://www.cosmopolitan.com/health-fitness/a29107622/alzheimers-gene/

[4] Karch, Celeste M. and Alison M. Goate. 2015. Alzheimer’s Disease Risk Genes and Mechanisms of Disease Pathogenesis. Vol. 77. doi:https://doi.org/10.1016/j.biopsych.2014.05.006.  http://www.sciencedirect.com/science/article/pii/S0006322314003394.

[5] Younger/Early-Onset Alzheimer’s. Alzheimer’s Association. Retrieved from https://www.alz.org/alzheimers-dementia/what-is-alzheimers/younger-early-onset

[6] Roses, Allen D. and Ann M. Saunders. 1994. APOE is a Major Susceptibility Gene for Alzheimer’s Disease. Vol. 5. doi:https://doi.org/10.1016/0958-1669(94)90091-4. http://www.sciencedirect.com/science/article/pii/0958166994900914.

[7] Ridge, PG, Hoyt, KB, Boehme, K et al. 2016. Assessment of the genetic variance of late-onset Alzheimer’s disease. Neurobiol Aging. Vol. 41 doi.org/10.1016/j.neurobiolaging.2016.02.024.

[8] Popejoy, AB, and Fullerton, SM. 2016. Genomics is failing on diversity. Nature, 538(7624), 161–164. https://doi.org/10.1038/538161a

[9] Blue EE, Horimoto ARVR, Mukherjee S, Wijsman EM, Thornton TA. 2019. Local ancestry at APOE modifies Alzheimer’s disease risk in Caribbean Hispanics. Alzheimer’s & Dementia: the Journal of the Alzheimer’s Association. Vol. 12. doi.org/10.1016/j.jalz.2019.07.016

[10] Andrews, Shea J., Brian Fulton-Howard, and Alison Goate. 2020. Interpretation of Risk Loci from Genome-Wide Association Studies of Alzheimer’s Disease. Vol. 19. doi:https://doi.org/10.1016/S1474-4422(19)30435-1. http://www.sciencedirect.com/science/article/pii/S1474442219304351.