Spinal Fracture

A spinal fracture, also known as a vertebral fracture, refers to a break in one or more of the bones (vertebrae) that make up the spinal column. These fractures can range from minor cracks to severe breaks that can compromise the integrity of the spine and potentially injure the spinal cord. While often associated with high-impact trauma, such as falls or motor vehicle accidents, spinal fractures can also occur due to underlying conditions that weaken the bone, most notably osteoporosis.

Biological Basis

The biological susceptibility to spinal fractures is multifaceted. While traumatic events are a direct cause, an individual’s bone health significantly influences the likelihood and severity of a fracture. Genetic factors play a crucial role in determining bone mineral density (BMD) and overall bone strength, which are key determinants of fracture risk. Genes involved in bone formation, remodeling, and calcium metabolism, such as those related to vitamin D receptors (VDR) or Wnt signaling pathway components like LRP5, can influence an individual’s predisposition to conditions like osteoporosis. Variations in these genes can lead to lower peak bone mass or accelerated bone loss, increasing the risk of fragility fractures, particularly in the spine. The structural integrity of collagen, a major component of bone matrix, also has a genetic basis, with variations impacting bone elasticity and strength.

Clinical Relevance

Spinal fractures present a significant clinical challenge due to their potential for severe pain, disability, and neurological complications. Symptoms can include sudden, sharp back pain, muscle weakness, numbness, or tingling if the spinal cord or nerves are affected. Diagnosis typically involves imaging techniques such as X-rays, CT scans, and MRI. Treatment strategies vary widely depending on the type and severity of the fracture, ranging from conservative management with pain medication and bracing to surgical intervention to stabilize the spine, decompress neural structures, or correct deformities. Early and accurate diagnosis is critical to prevent further injury and optimize recovery, as untreated or improperly managed fractures can lead to chronic pain, kyphosis (a hunchback deformity), and persistent neurological deficits.

Social Importance

Spinal fractures carry substantial social importance due to their impact on individual quality of life and the broader healthcare system. For individuals, these fractures often result in prolonged periods of pain, reduced mobility, and a significant loss of independence, affecting their ability to perform daily activities, work, and engage in social interactions. The psychological burden can also be considerable, with increased risks of depression and anxiety. From a societal perspective, spinal fractures contribute to a substantial healthcare burden, including costs associated with emergency care, surgery, hospitalization, rehabilitation, and long-term care. They are a major cause of disability, particularly among the elderly population where osteoporosis-related vertebral fractures are common, leading to a demand for public health initiatives focused on fracture prevention, early detection, and effective management strategies.

Methodological and Statistical Constraints

Studies on spinal fracture face several methodological and statistical constraints that can influence the interpretation of genetic associations. Many investigations, particularly those with smaller sample sizes, may be underpowered to identify genetic variants with low allele frequencies or modest effect sizes, potentially leading to an incomplete understanding of the genetic architecture of spinal fracture . Understanding the role of specific variants and their associated genes provides insight into the underlying mechanisms of spinal fracture predisposition.

The rs10190845 variant is located in an intergenic region between the FBLN7 and ZC3H8 genes. FBLN7(Fibrillin-like 7) encodes a protein that is part of the fibrillin family, essential components of the extracellular matrix (ECM), which provides structural support and elasticity to tissues, including bone. Alterations in ECM proteins can affect bone quality and strength, potentially influencing susceptibility to fractures.ZC3H8(Zinc Finger CCCH-Type Containing 8) is a gene that typically functions as an RNA-binding protein involved in gene regulation, which could indirectly impact bone development or maintenance by controlling the expression of genes critical for osteoblast or osteoclast activity.^[1] Variations near or within these genes, such as rs10190845 , may modulate their expression or function, thereby contributing to differences in bone health and fracture risk.

Another variant, rs1493960 , is associated with the MICAL2 gene, while rs2290492 is linked to ST8SIA2. MICAL2(Microtubule Associated Monooxygenase, Calponin And LIM Domain Containing 2) plays a role in regulating the cytoskeleton, cell migration, and various signaling pathways, including those vital for bone formation and remodeling, such as the Wnt pathway. Disruptions in these processes can lead to impaired bone development or maintenance, increasing fracture risk.ST8SIA2(ST8 Alpha-N-Acetyl-Neuraminide Alpha-2,8-Sialyltransferase 2) is involved in the synthesis of gangliosides, which are crucial for cell surface interactions and neuronal signaling, potentially influencing the neural regulation of bone metabolism or cell communication within bone tissue.^[2] Variations like rs1493960 and rs2290492 could affect the expression or activity of these genes, thereby influencing bone strength and resilience, making individuals more or less prone to spinal fractures.

The variant rs7121756 is located in a region encompassing the OR5BD1P and CYCSP26 genes, both of which are pseudogenes. Pseudogenes are non-functional copies of genes, but they can sometimes play regulatory roles, for example, by acting as decoys for microRNAs or by modulating the expression of their functional counterparts. While their direct protein-coding function is typically absent, genetic variations within pseudogenes or their regulatory regions can still have an impact on the expression of nearby functional genes or other related pathways.^[3]Such indirect effects could influence processes related to bone homeostasis, potentially contributing to an individual’s overall bone mineral density and their susceptibility to conditions like osteoporosis and subsequent spinal fractures.^[4]

Defining Spinal Fractures and Associated Terminology

Spinal fractures, often referred to as vertebral fractures in research, represent a critical health concern characterized by a break in one or more vertebrae. These fractures are frequently associated with underlying conditions such as osteoporosis, leading to what are termed “osteoporotic fractures”.^[5] The clinical significance of these fractures is substantial, particularly when they occur due to low-trauma events, which differentiates them from fractures resulting from high-impact injuries.^[5] Understanding the precise definition and nomenclature is crucial for accurate diagnosis, research, and public health initiatives.

Osteoporotic fractures, including vertebral fractures, are defined by excessive skeletal fragility and susceptibility to fractures from minimal trauma, particularly among the elderly.^[5]While hip fractures are noted as a severe and fatal outcome of osteoporosis, vertebral fractures specifically target the spinal column.^[5] The term “osteoporotic fractures” serves as a broader category encompassing various skeletal sites, with “vertebral fractures” specifying the location within the spine. This distinction is vital for epidemiological studies and targeted interventions.

Classification by Etiology and Trauma Level

Classification systems for spinal fractures often differentiate based on their etiological factors and the level of trauma involved. A primary distinction is made between low-trauma fractures, which are typically indicative of underlying bone fragility conditions like osteoporosis, and high-trauma fractures, which result from significant external forces.^[6]In research settings, particularly for genetic studies of osteoporosis, subjects with high-trauma fractures are often excluded to enhance the signal from genetic factors influencing bone mass and structure.^[6]Further refinement in classification involves considering conditions and medications that can affect bone metabolism and structure, thereby influencing fracture risk. For instance, individuals with serious metabolic diseases (e.g., diabetes, hyper-parathyroidism, hyperthyroidism), other skeletal diseases (e.g., Paget disease, osteogenesis imperfecta, rheumatoid arthritis), or those chronically using drugs affecting bone metabolism (e.g., hormone replacement therapy, corticosteroids, anti-convulsants) are typically excluded from studies focusing on primary osteoporosis and related fractures.^[5]This rigorous exclusion process ensures that classifications accurately reflect the specific disease etiology under investigation, minimizing confounding environmental and therapeutic factors.

Diagnostic Approaches and Risk Assessment

The diagnosis and assessment of spinal fractures, particularly vertebral fractures, rely on a combination of clinical criteria and approaches. Vertebral fractures can be identified through self-reporting in detailed questionnaires, with classification accuracy enhanced by integrating additional hospital data.^[6] This approach helps to confirm the presence of fractures and distinguish them based on their context, such as excluding high-trauma events or cases influenced by specific medications or conditions.

A crucial approach for quantifying the risk of osteoporotic fractures, including those in the spine, is Bone Mineral Density (BMD).^[5]BMD measurements are commonly performed at various skeletal sites, including the lumbar spine (LSBMD) and hip (femoral neck BMD), with hip BMD being particularly relevant to the risk of hip fracture.^[3]Other measures, such as quantitative ultrasound (e.g., broadband ultrasound attenuation or BUA of the calcaneus) and femoral geometry measures, also contribute to a comprehensive assessment of bone health and fracture susceptibility.^[3]Furthermore, biomarkers like serum undercarboxylated osteocalcin have been identified as markers for fracture risk in elderly women, offering additional insight into bone metabolism and fragility.^[7]

Causes

Spinal fractures, often occurring in the context of weakened bone structure, result from a complex interplay of genetic predispositions, environmental factors, and various physiological stressors. These fractures can significantly impact an individual’s mobility and quality of life, highlighting the importance of understanding their underlying causes.

Genetic Predisposition to Bone Weakness

Genetic factors play a substantial role in determining an individual’s bone mineral density (BMD) and susceptibility to spinal fractures. Genome-wide association studies (GWAS) have identified numerous genetic loci associated with BMD, indicating a polygenic risk for bone fragility.^[4] For instance, sequence variants in genes such as PTCH1 have been specifically linked to spine BMD and osteoporotic fractures.^[8] Other candidate genes influencing human BMD include ADAMTS18 and TGFBR3, which have been identified in various ethnic groups.^[2]Further genetic associations include polymorphisms in the Vitamin D Receptor (VDR) gene (specifically the Cdx2 polymorphism) with vertebral fracture risk, the Sp1 polymorphism of Collagen Type I a-1 (COL1A1) with BMD, and several single nucleotide polymorphisms (SNPs) in Low Density Lipoprotein Receptor-Related Protein 5 (LRP5) with BMD.^[2]These inherited variants can influence bone formation, remodeling, and matrix integrity, thereby altering the mechanical strength of the vertebrae and increasing vulnerability to fracture, even from low-impact trauma. The cumulative effect of these genetic variations contributes to an individual’s overall bone health profile.^[8]

Environmental and Nutritional Factors

Environmental and lifestyle choices significantly modulate bone health and, consequently, the risk of spinal fractures. Nutritional deficiencies, particularly a lack of essential vitamins, can compromise bone integrity. For example, Vitamin K plays a crucial role in bone metabolism, and its adequate intake has been linked to the prevention of fractures.^[9]This vitamin is essential for the carboxylation of osteocalcin, a protein involved in bone mineralization, and insufficient levels can lead to undercarboxylated osteocalcin, which is a marker for increased hip fracture risk in elderly women.^[7]Beyond diet, broader environmental influences and socioeconomic factors can indirectly affect bone health by impacting access to nutritious food, opportunities for physical activity, or exposure to sunlight for Vitamin D synthesis. The interplay between these external factors and an individual’s genetic makeup can either mitigate or exacerbate the inherent risk of developing fragile bones, highlighting the importance of a holistic approach to fracture prevention.

Age-Related Changes and Comorbid Conditions

Advancing age is a primary non-modifiable risk factor for spinal fractures, predominantly due to age-related bone loss and the increased prevalence of osteoporosis, particularly in elderly women.^[7]As individuals age, the balance between bone formation and resorption shifts, leading to a progressive decrease in bone mineral density and architectural deterioration, making the spine more susceptible to fractures.^[6]Furthermore, various comorbid medical conditions can significantly contribute to the risk of spinal fractures. Conditions such as chronic obstructive pulmonary disease (COPD) are associated with osteoporosis, where systemic inflammation and medication effects can impair bone metabolism.^[10]Arterial stiffness, a common comorbidity, has also been linked to osteoporosis, suggesting a shared underlying pathophysiology that may involve vascular calcification and bone health.^{[10], [11]}Additionally, osteoarthritis of the spine can alter spinal biomechanics, potentially increasing stress on vertebral bodies and contributing to fracture risk.^[6]

Biological Background of Spinal Fracture

Spinal fractures represent a significant health concern, often resulting from trauma, but also influenced by underlying biological factors that affect bone strength, healing capacity, and overall skeletal integrity. The complex interplay of molecular pathways, genetic predispositions, cellular functions, and tissue-level processes determines an individual’s susceptibility to these injuries and their ability to recover. Understanding these biological underpinnings is crucial for prevention, diagnosis, and treatment strategies.

Bone Homeostasis and Structural Integrity

The strength and integrity of spinal bones are maintained through a dynamic process called bone homeostasis, involving continuous bone formation and resorption. Key biomolecules and cellular pathways regulate this balance. For instance, theADAMTS18gene, which encodes for ADAM metallopeptidase with thrombospondin type 1 motif, 18, has been identified as a bone mass candidate gene. Studies indicate that decreasedADAMTS18expression in vivo may contribute to the non-healing of skeletal fractures, suggesting its crucial role in bone repair and remodeling.^[2] Furthermore, specific genetic variations, such as the minor allele of ADAMTS18 SNP rs16945612 , are hypothesized to repress ADAMTS18expression, thereby influencing bone mineral density (BMD) and potentially increasing susceptibility to osteoporosis phenotypes.^[2]

Molecular Signaling in Bone Development and Repair

Transforming Growth Factor-beta (TGF-b) signaling pathways are central to bone biology, playing vital roles in cell growth, differentiation, and tissue repair.TGFBR3(transforming growth factor, beta receptor III) is a major mediator of these pathways and also functions as a cell-surface receptor for Bone Morphogenetic Proteins (BMPs).^[2] Notably, TGFBR3 can modulate the biological function of BMP2, a well-established key factor in bone biology significantly associated with BMD phenotypes.^[2] The importance of TGFBR3 is underscored by findings that its levels are significantly lower in subjects with normal skeletal fractures compared to those with nonunion fractures, and TGFBR3 knockout mice exhibit severe abnormal skeletal defects, highlighting its indispensable role in skeletal development and healing.^[2]

Cellular and Epigenetic Regulation of Bone Health

Cellular processes such as proliferation, differentiation, migration, and signaling are fundamental to bone formation and repair. Mesenchymal stem cells and embryonic stem cells, crucial for tissue regeneration, show significant enrichment of epigenetic marks like H3K4me1 and H3K4me3, which are associated with enhancer and promoter sites, respectively.^[12] Active promoters, marked by H3K9ac, are also enriched in these cell types, as well as in epithelial cells, blood, and T cells.^[12]These epigenetic modifications, including DNA methylation, influence gene expression and regulation, varying with age and tissue type, and are increasingly recognized for their role in the pathogenesis of various conditions, including bone-related traits.^[13] The cytoskeleton, a dynamic network within cells, is also essential for these cellular processes, and its proper organization is vital for tissue development and function, with dysregulation linked to various diseases.^[14]

Pathophysiological Processes and Fracture Outcomes

Spinal fractures can range from those that heal normally to non-union fractures, which fail to heal six months after injury. The distinction between these outcomes is often linked to the underlying biological environment and genetic factors. For instance, both ADAMTS18 and TGFBR3 genes are differentially expressed in subjects with normal skeletal fracture compared to those with nonunion skeletal fracture, suggesting their direct involvement in the healing process.^[2]Genetic associations have also been found for conditions that predispose individuals to spinal fractures, such as osteoporosis with vertebral fractures, and factors influencing bone mineral density of the spine.^[6] These pathophysiological processes highlight how genetic predispositions and molecular dysregulations can impair the body’s natural compensatory responses, leading to poor fracture healing or increased susceptibility.

Genetic Determinants of Ischemic Stroke Prognosis and Functional Recovery

Genetic research offers significant prognostic value in predicting outcomes and understanding disease progression following ischemic stroke. Studies have identified genetic variants, such as low frequency variants in thePATJgene, that are associated with a worse functional outcome after ischemic stroke.^[15]These findings, often derived from genome-wide association meta-analyses (GWAS) adjusted for critical factors like age, sex, ancestry, and baseline stroke severity (NIHSS), provide insights into the biological pathways influencing recovery, typically assessed using the modified Rankin Scale (mRS) at three months post-stroke.^[16] While such findings are exploratory and require replication in independent cohorts, they underscore the potential for genetic markers to predict long-term implications and functional recovery trajectories, even if current outcome measures like the mRS are considered crude.^[16]The identification of these genetic influences can help clinicians anticipate individual patient responses and potential recovery challenges. Understanding genetic predispositions can aid in setting realistic patient and family expectations regarding post-stroke rehabilitation and long-term care needs, especially considering that the studied populations often reflect milder strokes, which might limit the detection of factors influencing a wider range of recovery.^[16]Furthermore, genetic drivers of factors like von Willebrand Factor levels have been associated with the risk for recurrent stroke, indicating a potential role in predicting future cerebrovascular events.^[17]

Advanced Risk Stratification and Clinical Applications in Stroke Care

The integration of genetic information into clinical practice holds promise for advanced risk stratification and personalized medicine approaches in stroke management. Genetic variants can enhance risk assessment beyond traditional clinical factors, leading to improved identification of high-risk individuals for adverse outcomes or recurrent events.^[17]For instance, the inclusion of genetic markers has been shown to result in a net reclassification improvement (NRI) of 10.6% (p=0.0028) and a continuous NRI of 19.7% (p=0.0113) in predicting recurrent stroke risk, signifying a substantial benefit in appropriately reclassifying patient risk.^[17]These applications extend to diagnostic utility, where gene-based analyses and expression quantitative trait loci (eQTLs) help link genetic variants to gene expression patterns, providing a deeper understanding of underlying disease mechanisms.^[16]Such insights can eventually inform treatment selection, guiding clinicians towards therapies that may be more effective for individuals with specific genetic profiles. While current studies often lack data on acute therapies and rehabilitation outcomes, future research incorporating these elements could further refine personalized monitoring strategies and preventative interventions based on an individual’s genetic predisposition to stroke and its functional consequences.^[16]

Interplay of Genetic Susceptibility and Comorbidities in Stroke Outcomes

Stroke outcomes are complex, influenced by an intricate interplay between genetic susceptibility and various comorbidities and associated conditions. Research has highlighted shared genetic susceptibility between ischemic stroke and other cardiovascular diseases, such as coronary artery disease, suggesting overlapping pathological pathways.^[18]Furthermore, specific genetic variations, like those at 16q24.2, have been linked to particular stroke subtypes, such as small vessel stroke, indicating the potential for genetically informed sub-classification of disease.^[13]Beyond genetics, baseline characteristics such as age, sex, hypertension, diabetes mellitus, hyperlipidemia, and cigarette smoking are well-established confounders that significantly impact stroke risk and outcome.^[19]While genetic studies typically adjust for these clinical factors, the comprehensive understanding of how genetic variants interact with these comorbidities to modulate functional recovery remains an important area of ongoing investigation. This holistic approach, considering both inherited predispositions and acquired risk factors, is crucial for developing more effective prevention strategies and tailored management plans that address the full spectrum of stroke pathology and patient heterogeneity.^[16]

Key Variants

RS ID	Gene	Related Traits
rs10190845	FBLN7 - ZC3H8	spinal fracture
rs1493960	MICAL2	spinal fracture
rs2290492	ST8SIA2	spinal fracture
rs7121756	OR5BD1P - CYCSP26	spinal fracture

Frequently Asked Questions About Spinal Fracture

These questions address the most important and specific aspects of spinal fracture based on current genetic research.

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1. My mom broke her spine, am I doomed to break mine too?

Not necessarily. While genetic factors play a significant role in bone strength, including genes likeVDR and LRP5that influence bone mineral density, having a family history doesn’t mean it’s inevitable. Your lifestyle choices, like diet and exercise, can significantly impact your bone health and help mitigate genetic predispositions.

2. Why did my friend fall harder but I broke my back easily?

Your individual bone health is strongly influenced by your genetics, which determine your bone mineral density and overall strength. Variations in genes affecting bone formation, remodeling, or the structural integrity of collagen can make your bones more fragile, increasing your risk of fracture even from minor trauma compared to someone with genetically stronger bones.

3. Does getting older mean my bones will just break more easily?

While bone loss naturally accelerates with age, the rate and severity of this process are partly determined by your genetics. Your genes influence your peak bone mass achieved earlier in life and how quickly you lose bone, meaning some people are more predisposed to age-related conditions like osteoporosis and subsequent fractures.

4. Can I overcome my family’s “weak bones” with exercise and diet?

Yes, you can significantly influence your risk. While genetic factors related to genes like VDR and LRP5impact your inherent bone strength, environmental factors and lifestyle choices are crucial. Regular weight-bearing exercise, a diet rich in calcium and vitamin D, and other healthy habits can help build and maintain bone density.

5. I’m not European, does my background affect my fracture risk?

Yes, it can. Genetic diversity and patterns of genetic risk vary across different ancestral groups. Much of the research on genetic factors for spinal fractures has focused on populations of European descent, meaning associations identified in those groups may not be directly transferable or fully informative for people from other backgrounds.

6. Is a DNA test worth it to check my fracture risk?

Genetic testing can identify variations in specific genes, such as VDR or LRP5, that are known to influence bone health and fracture risk. However, spinal fracture risk is complex, involving many genes and significant environmental factors, so a single test may only provide part of your overall risk profile.

7. Why do some people never break bones, no matter what they eat?

An individual’s inherent bone strength is heavily influenced by their genetic makeup. Some people inherit genes that provide a naturally higher peak bone mass and more robust bone structure, making them less susceptible to fractures even if their dietary habits aren’t always optimal.

8. My sibling has strong bones, but mine are weaker. Why the difference?

Even within the same family, individual genetic variations can lead to differences in bone health. Factors like unique combinations of genes (gene-gene interactions), rare genetic variants, and differing environmental exposures or lifestyle choices between siblings can contribute to variations in bone density and strength.

9. What can I do now to keep my spine strong later on?

To maintain a strong spine, focus on building and preserving bone mineral density throughout your life. This includes a balanced diet rich in calcium and vitamin D, regular weight-bearing and muscle-strengthening exercises, and avoiding habits like smoking, which can negatively impact bone health.

10. Is it true that only big falls cause fractures, not my genes?

That’s a common misconception. While severe trauma is a direct cause, your genetic makeup significantly influences your bone strength and fragility. Conditions like osteoporosis, which have a strong genetic component, can weaken bones to the point where even minor incidents, not just big falls, can lead to a spinal fracture.

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This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.

Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.

References

[1] Lu, S. “Bivariate genome-wide association analyses identified genetic pleiotropic effects for bone mineral density and alcohol drinking in Caucasians.”J Bone Miner Metab, vol. 36, no. 1, 2018, pp. 101-110.

[2] Xiong, D. H., et al. “Genome-wide association and follow-up replication studies identified ADAMTS18 and TGFBR3as bone mass candidate genes in different ethnic groups.”Am J Hum Genet, vol. 84, no. 3, 2009, pp. 384-392.

[3] Kiel DP, et al. “Genome-wide association with bone mass and geometry in the Framingham Heart Study.”BMC Med Genet, vol. 8, no. Suppl 1, 2007, p. S14.

[4] Rivadeneira, F., et al. “Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies.”Nat Genet, vol. 41, no. 11, 2009, pp. 1199-1206.

[5] Liu YZ, et al. “Powerful bivariate genome-wide association analyses suggest the SOX6 gene influencing both obesity and osteoporosis phenotypes in males.”PLoS One, vol. 4, no. 8, 2009, p. e6827.

[6] Bjornsdottir G, et al. “Sequence variant at 8q24.21 associates with sciatica caused by lumbar disc herniation.” Nat Commun, vol. 9, no. 1, 2018, p. 797.

[7] Szulc P, et al. “Serum undercarboxylated osteocalcin is a marker of the risk of hip fracture in elderly women.”J Clin Invest, vol. 91, no. 4, 1993, pp. 1769-1774.

[8] Styrkarsdottir, U., et al. “Sequence variants in the PTCH1gene associate with spine bone mineral density and osteoporotic fractures.”Nat Commun, vol. 7, 2016.

[9] Cockayne, S., Adamson, J., Lanham-New, S., Shearer, M. J., Gilbody, S., Torgerson, D. J. “Vitamin K and the prevention of fractures: systematic review and meta-analysis of randomized controlled trials.”Arch Intern Med, vol. 166, 2006, pp. 1256–1261.

[10] Sabit, R., Bolton, C. E., Edwards, P. H., Pettit, R. J., Evans, W. D., McEniery, C. M., et al. “Arterial stiffness and osteoporosis in chronic obstructive pulmonary disease.”Am J Respir Crit Care Med, vol. 175, 2007, pp. 1259–1265.

[11] Mitchell, G. F., et al. “Common genetic variation in the 3’-BCL11Bgene desert is associated with carotid-femoral pulse wave velocity and excess cardiovascular disease risk: the AortaGen Consortium.”Circ Cardiovasc Genet, vol. 4, no. 1, 2011, pp. 52-60.

[12] Malik, R et al. “Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.”Nat Genet, 2018, PMID: 29531354.

[13] Traylor, M et al. “Genetic variation at 16q24.2 is associated with small vessel stroke.”Ann Neurol, 2017, PMID: 27997041.

[14] Vojinovic, D., et al. “Genome-wide association study of 23,500 individuals identifies 7 loci associated with brain ventricular volume.” Nat Commun, vol. 9, no. 1, 2018, p. 3943.

[15] Mola-Caminal, M et al. “PATJ Low Frequency Variants Are Associated With Worse Ischemic Stroke Functional Outcome.”Circ Res, 2019, PMID: 30582445.

[16] Soderholm, M et al. “Genome-wide association meta-analysis of functional outcome after ischemic stroke.”Neurology, 2019, PMID: 30796134.

[17] Williams, SR et al. “Genetic Drivers of von Willebrand Factor Levels in an Ischemic Stroke Population and Association With Risk for Recurrent Stroke.”Stroke, 2017, PMID: 28495826.

[18] Dichgans, M et al. “Shared genetic susceptibility to ischemic stroke and coronary artery disease: a genome-wide analysis of common variants.”Stroke, 2013, PMID: 24262325.

[19] Hong, EP et al. “Genomic Variations in Susceptibility to Intracranial Aneurysm in the Korean Population.”J Clin Med, 2019, PMID: 30823506.