Johann Gregor Mendel (1822-1884) developed the concept of genes and inheritance through his work on pea plants ( Roberts 1929). The inception of the Human Genome Project (HGP) was first put on paper in 1988 and aimed to map all human genes. It took over 30 years to complete and the final gapless assembly was finished in January 2022. The main goals of the HGP were to determine the correct sequence of 3 billion nucleotide that makes up the whole of human DNA and to find all human genes, sequence the entire genome, and eliminate disease-causing genes. Genome-wide association studies (GWAS) are blueprints that are used to link recognizable associations between genetic variants and diseases among the people, which could eventually predict the occurrence of diseases and identify ideal prevention strategies and treatment modalities. This has led to an increase in GWAS in many countries to identify heritable phenotypes and to institute therapeutic interventions ( Uffelmann et al. 2021). To date, GWAS have been carried out on millions of people and have identified 40 diseases that are influenced by the genes they carry ( Manolio et al. 2008) .

Many GWAS have been carried out to find the genetic influence on orthopedic diseases that run in families, such as adolescent idiopathic scoliosis (AIS) ( Kou et al. 2019; Man et al. 2019; Khanshour et al. 2018), developmental dysplasia of the hip (DDH) ( Hatzikotoulas et al. 2018), osteoarthritis of the knee (OAK) ( Zengini et al. 2018; Soul et al. 2018), osteoarthritis of the hip (OAH) ( Styrkarsdottir et al. 2017; Evans et al. 2015), and osteoporosis-related fragility fractures ( Guo et al. 2012). The objective of this review is to report the GWAS performed on all orthopedic diseases and to ascertain whether any preventive strategies and treatments were established and succeeded.

Between 2005 and May 2022, we searched in MEDLINE, Scopus, Web of Science, EMBASE, Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews and the Science Citation Index with the following key words: orthopedics, Human Genome Project, GWAS, target genes and clinical translation. We supplemented our searches by manually reviewing the bibliographies of eligible studies and relevant review articles. Keywords were used instead of full sentences or questions in multiple search boxes. The keywords were supplemented with synonyms combined by “OR” and all forms of a keywords were garnered by using an asterisk symbol (*) after the root of a keyword. The database search limits were for English Language only.

The inclusion criteria included studies involving patients that were published in the English language. The exclusion criteria included review articles and correspondence.

The data was retrieved to find out the number of studies performed, the specific diseases identified and the total number of subjects screened. We pooled the numbers of each disease studied and compared the diseases and number of subjects. Lastly, the data was meticulously searched for any recommended preventive strategies and suggestive treatments. All of the articles were reviewed by the author for risk of bias, who found no discrepancies in the papers selected because only the presence or absence of the gene and SNP was considered. This review was done in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines ( Moher et al. 2009; Sadat-Ali & Sadat-Ali 2022).

There were 53,652 GWAS that reported on the Human Genome Project, out of which 439 studies reported on GWAS and orthopedics. After the inclusion and exclusion criteria were considered, 38 studies with data from 1,489,834 patients were analyzed ( Figure 1). Table 1 displays the data from those 38 studies. In total, 21 orthopedic conditions were studied, with the majority being osteoarthritis (867,648), back pain (158,000), AIS (125,015), ligament injuries (102,979), bone mineral density (BMD) (64,765) and osteonecrosis of the femur head (60,217) ( Figure 2). Overall, 18 countries were represented in the studies, with the United States of America (16), United Kingdom (14) and China (14) being the most common ( Figure 3). Unfortunately, none of the studies were carried out in the Middle East. Based on the review, the GWAS were unable to predict any diseases but were able to help develop treatments for ankylosing spondylitis and osteoporosis.

This review shows that the Human Genome Project and GWAS have done tremendous work in genetic mapping many diseases in general and a few common orthopedic diseases. The GWAS on osteoarthritis (OA), which affects more than 300 million people around the world, has some positive findings and identifies 100 independently associated risk variations, out of which 52 were not described or known to be associated with OA ( Boer et al. 2021). The other sites of osteoarthritis, such as the hip and knee, were also studied ( Soul et al. 2018; Styrkarsdottir et al. 2017; Evans et al. 2015; Panoutsopoulou et al. 2017). Osteoarthritis of the knee (OAK) was reported to be common in over 53% of men and 60.9% of women in Saudi Arabian populations and has continued to increase. In 2011, funding was requested by the author but not awarded to assess the association between genetic polymorphisms and OA among Saudi Arabian men and women. ( Al-Omran, Sadat-Ali and AlHammam 2011).

AIS was the second most common disease that the GWAS found was genetically influenced. It affects 0.47-5.2% of healthy children and during growth spurts, the curves increase ( Konieczny et al. 2013). Overall, 25 different loci were identified in a variety of ethnic groups ( Kou et al. 2019; Man et al. 2019; Khanshour et al. 2018; Zhu et al. 2015; Grauers et al. 2015). Further sub group analysis highlighted two SNPs (rs1190870 and rs678741) that were significantly associated with the presence of right thoracic curves ( Man et al. 2019). None of the studies were conducted on Middle Eastern populations, even though a target gene and three SNPs were identified for AIS in the Saudi Arabian population ( Sadat-Ali et al. 2011; Al-Othman et al. 2017). In the Middle East, most female children remain covered from the neck down, allowing the AIS to remain undetected until it’s too late. A clinical translation of the GWAS could promote early diagnosis of AIS and prevent surgery that causes tremendous morbidity.

Developmental dysplasia of the hip (DDH) was another disease that the GWAS examined. Hatzikotoulas et al. (2018) performed a GWAS on DDH in the United Kingdom and reported that there is strong genetic association locus at GDF5 (rs143384). At the same time, the author and his associates in Saudi Arabia conducted a study with 473 subjects (100 patients, 200 parents, 73 siblings and 100 healthy controls) ( Sadat-Ali et al. 2018) and reported that there was a definite relationship between GDF5 (SNP rs143383) and DDH. For the first time, it was found that the genotype TT and the T allele were overly expressed in the patients and the fathers. In the United Kingdom, it was reported that 1-2 babies out of 1000 require DDH treatment ( https://www.nhs.uk/conditions/developmental-dysplasia-of-the-hip/ ). A recent meta-analysis found that in Saudi Arabia, incidence of DDH was 10.46 out of 1000, and in over 40% of patients was the result of family history. The meta-analysis found an average of 22,336 cases at any given time in the country with 7,119 new cases added yearly ( Sadat-Ali 2020). Many cases of DDH are clustered in specific towns and cities. If the GWAS can be clinically translated, early diagnosis will provide clinically beneficial improvements in patient care and ensure that children can have non-surgical DDH treatment, which could limit the long term morbidity and complications of surgical treatments.

The other diseases that GWAS showed were genetically influenced and common in clinical practice included back pain, ligament injuries, osteonecrosis of femur heads and osteoporosis related issues. Clinical translation based on GWAS could improve prediction and progression for some diseases. These studies could identify therapeutic targets leading to therapeutic agents. Unfortunately, even after screening over a million patients, the benefits in drug discovery were inappreciable. From an orthopedic surgeon’s perspective, GWAS linked two genes that were identified as RANKL/ESR1 and TNFR1/PTGER4/TYK2. The former allowed drugs like denosumab, a potent antiresorptive, to be developed, whereas the other allowed fostamatinib to be developed for ankylosing spondylitis ( Schwarz and Ritchlin 2007; Tak and Kalden 2011).

On the aspect of disease prediction, Scolioscore ^TM is supposed to identify patients whose curve will progress in AIS ( Visscher et al. 2017). Unfortunately, the independent validation could not confirm this ( Carlson 2011).

Our study has certain limitations. First, we did not discuss all of the orthopedics diseases reported in the GWAS in this review in detail. Second, the review showed that a limited number of diagnostic procedures could predict the diseases based on the GWAS studies. Moreover, the Scolioscore ^TM that could predict the progression of curves in AIS that came out of these studies still needs to be independently validated. Compared to the rest of the world, GWAS in Middle Eastern countries are so low that the magnitude of reports is markedly incomparable (99.99 to 0.01%) ( Suri et al. 2018).

In conclusion, HAP and GWAS have produced and identified many novel loci that can cause disease processes. Many more studies are being conducted to find new loci and genetic ancestries and these studies were expected to help predict diseases and develop new diagnostic methods, preventive strategies and better clinical care, but this has not happened yet. Our review showed that a limited number of drugs came into existence based on the GWAS studies. One test that could predict the progression of curves in AIS came out of these studies, but it still needs to be independently validated. It appears that we must continue investigating instead of translating this knowledge to improve patient care.