🧬🚶🏼‍♀️Is Osteoporosis Hereditary?

A Short Introduction

This is another blog post in a series where I will focus on the genetics of multiple complex traits, such as longevity and others, but also complex diseases, such as psoriasis and many more.

In this one, I will focus on osteoporosis. In short, I will shortly introduce what osteoporosis is, what causes osteoporosis, why it is essential, and finally, focus on the genetics of osteoporosis, which is the main topic, I already mentioned.

For the purpose of this blog post, I performed an exploratory analysis. I collected data from 14 genome-wide association studies (GWAS) focused on identifying genes associated with osteoporosis-related traits. The final output of this analysis is a summary with a list of genetic variants (genetic mutations) and genes that are most commonly reported in those GWAS studies.

What Is Osteoporosis?

Osteoporosis is a common disease with a strong genetic component characterized by the weakening of bones, making them fragile and more prone to fractures. Osteoporosis occurs when the creation of new bone doesn't keep up with the removal of old bone. Bones become so brittle that mild stresses like bending over or lifting can cause a fracture. The most common fractures associated with osteoporosis occur in the hip, wrist, and spine.

There are two basic types of osteoporosis:

1. Primary osteoporosis can be divided into postmenopausal osteoporosis (type 1) and senile osteoporosis (type 2).

   1. Type 1 (postmenopausal osteoporosis) occurs in women after menopause due to a decrease in estrogen levels. Estrogen is known to help in maintaining bone density.

   2. Type 2 (senile osteoporosis) generally occurs after the age of 70 and affects both men and women and the bone loss results from aging and a deficiency in calcium and vitamin D.

2. Secondary osteoporosis is caused by certain medical conditions or treatments that interfere with attaining peak bone mass and lead to bone loss. These include long-term use of medications like corticosteroids, certain cancers, rheumatoid arthritis, hyperparathyroidism, and lifestyle factors such as alcoholism or anorexia nervosa.

What Causes Osteoporosis?

Multiple risk factors can lead to osteoporosis, such as: 

1. Age: as people age, bone resorption (breakdown) gradually overtakes bone formation, leading to bone loss.

2. Hormonal imbalances. This is especially the case with the reduced estrogen levels in women during menopause but also reduced testosterone levels in men.

1. Genetic factors: A family history of osteoporosis can increase risk, and this is basically what this blog post will mainly cover, which is trying to understand the genetics underlying the development of osteoporosis.

2. Nutritional factors. Insufficient intake of calcium and vitamin D plays a vital role in the potential development of osteoporosis, which is essential for bone health.

3. Physical inactivity, such as a sedentary lifestyle, contributes to weaker bones.

4. Excessive alcohol and tobacco use as these can weaken bone health.

5. Also, certain medications and medical conditions as already mentioned in secondary osteoporosis, drugs (like corticosteroids) and conditions can lead to bone loss

However, in this blog post, I will mainly focus, as you would expect, on the primary type of osteoporosis and its genetic component.

So, Is Heritable Osteoporosis?

Studies of twins and families reveal that factors influencing the risk of bone fractures, like bone mineral density, bone ultrasound properties, and bone structure and turnover, are largely inherited. While the tendency to experience osteoporotic fractures is also hereditary, its influence decreases with age due to environmental factors like the likelihood of falling. The risk of developing osteoporosis is determined by numerous genetic variations and how they interact with environmental aspects like diet and exercise (Figure 1).

Figure 1: The main risk factors leading to the onset of osteoporosis

Significant progress in finding genes that control bone density has been made by studying rare genetic bone diseases. These diseases show significant bone differences caused by gene variations with solid effects. 

Large-scale studies have discovered many common, small-impact genetic variations that affect bone density and fracture risk in most people. Many of these genes and locations were not previously known to affect bone health. Despite a lot of progress in the past decade years in identifying these genes, there are still many more to find that influence bone characteristics. 

The bottom line is that osteoporosis exhibits a significant genetic component. In the rest of the post, I will cover what genes and corresponding genetic variants have been found to be associated with the potential onset of osteoporosis.

What Genes and SNPs Are Associated With Osteoporosis?

Since we have now established that genetics, among other things (diet and exercise), affects the development of osteoporosis, one would probably want to know what genetic variants (SNPs) and genes in which those variants are located are associated with the onset of osteoporosis. 

For that purpose, I performed an exploratory analysis where I acquired association data from the following large-scale genome-wide association studies focused on identifying genetic variants and genes being associated with osteoporosis:

1. Association between non-Caucasian-specific ASCC1 gene polymorphism and osteoporosis and obesity in Korean postmenopausal women.

2. Effect of dietary calcium on the gender-specific association between polymorphisms in the PTPRD locus and osteoporosis.

3. Genome-wide pleiotropy of osteoporosis-related phenotypes: the Framingham Study.

4. Common variants in a novel gene, FONG on chromosome 2q33.1 confer risk of osteoporosis in Japanese.

5. Genome-wide association study identifies ALDH7A1 as a novel susceptibility gene for osteoporosis.

6. Meta-analysis identifies a MECOM gene as a novel predisposing factor of osteoporotic fracture.

7. An integration of genome-wide association study and gene expression profiling to prioritize the discovery of novel susceptibility Loci for osteoporosis-related traits.

8. Powerful bivariate genome-wide association analyses suggest the SOX6 gene influencing both obesity and osteoporosis phenotypes in males.

9. The impact of non-additive genetic associations on age-related complex diseases.

10. A cross-population atlas of genetic associations for 220 human phenotypes.

11. Genome-wide Association Study Identified Chromosome 8 Locus Associated with Medication-related Osteonecrosis of the Jaw.

12. Genome-wide association study identifies genetic variants which predict the response of bone mineral density to teriparatide therapy.

13. A genome-wide association study meta-analysis of clinical fracture in 10,012 African American women.

14. Large-scale genome-wide association study in a Japanese population identifies novel susceptibility loci across different diseases.

These genetic studies linked genetics to various traits that serve as proxies or measures of osteoporosis, such as osteoporosis-related phenotypes, obesity, and osteoporosis, bisphosphonate-related osteonecrosis of the jaw in osteoporosis (oral bisphosphonate), response of lumbar spine BMD to teriparatide in osteoporosis, response of femoral neck BMD to teriparatide in osteoporosis, bone fracture in osteoporosis

Based on the association data from this set of studies, I performed an exploratory analysis and tried to answer the following questions:

1. How many genetic variants (SNPs) have been found to be associated with the onset of osteoporosis?

2. What genetic variants (SNPs) are most commonly associated with the onset of osteoporosis? 

3. How many and what genes have been found to be associated with the onset of osteoporosis?

4. What genes are most commonly associated with the onset of osteoporosis?

5. Finally, what can we learn about one's predisposition to osteoporosis by combining this data with my 23andMe raw genotype data?

So, let’s go!

How many and what genetic variants (SNPs) have been found to be associated with the onset of osteoporosis?

In total, 64 SNPs have been reported to be associated with osteoporosis.  Out of those 64 SNPs, none of them appeared more than once.

How many and what genes have been found to be associated with the onset of osteoporosis?

Out of those 64 unique SNPs associated with osteoporosis, 30 SNPs are not located in any specific gene but rather in intergenic regions, while the remaining 34 SNPs in some of the genes. 

What genes have the largest number of SNPs associated with the onset of osteoporosis?

Out of all genes containing SNPs that are highly associated with osteoporosis, only the following two had more than one highly associated SNP, and those are:

• The SOX6 gene with the following three SNPs: rs4756846,  rs297325, and rs112725769, and the other gene is

• The LRP5 gene harboring rs56154705 and rs880610.

What is the link between the SOX6 gene and osteoporosis?

The role of the SOX6 gene in osteoporosis is primarily connected to its function in cartilage formation and chondrocyte differentiation, which are essential for healthy bone development and maintenance. Abnormal SOX6 function can potentially disrupt these processes, contributing to the development or progression of osteoporosis.

What is the link between the LRP5 gene and osteoporosis?

The LRP5 gene’s role in the Wnt signaling pathway and its influence on osteoblast activity make it a key player in determining bone density and strength. Its function or dysfunction is directly linked to the risk and development of osteoporosis, making it a significant focus of research for understanding and treating this condition.