Abnormality Of The Nervous System

Introduction

The nervous system, an intricate network comprising the brain, spinal cord, and peripheral nerves, orchestrates virtually all bodily functions, including thought, movement, sensation, and emotion. An abnormality of the nervous system refers to any deviation from its typical structure, function, or development. These abnormalities can arise from a multitude of factors, leading to a broad spectrum of neurological and psychiatric conditions that can affect individuals across all age groups, from birth to old age. Such conditions can manifest as impairments in cognitive abilities, motor control, sensory perception, or emotional regulation, profoundly impacting an individual’s quality of life.

Biological Basis

The genesis of nervous system abnormalities is often complex and multifactorial, stemming from a dynamic interplay of genetic predispositions, environmental exposures, and developmental processes. Genetic factors, particularly common genetic variations like single nucleotide polymorphisms (SNPs), are increasingly recognized for their role in modulating an individual’s susceptibility to these conditions. Genome-wide association studies (GWAS) have been instrumental in identifying specific genetic loci associated with an elevated risk for various neurological disorders. For example, research has linked a specific genetic change in the TNIP1 gene and the presence of human leukocyte antigen-B*08 to an increased risk for myasthenia gravis^[1]. Similarly, multiple studies have identified several susceptibility loci across different chromosomes that contribute to the risk of developing glioma, a type of brain tumor ^[2]. Other neurological conditions with identified genetic associations include common variants linked to febrile seizures ^[3], risk genes for insomnia that also show genetic overlap with psychiatric and metabolic traits ^[4], and specific genetic markers associated with multiple system atrophy ^[5]. Elucidating these genetic underpinnings is crucial for understanding the molecular and cellular mechanisms that govern nervous system health and disease.

Clinical Relevance

The ability to identify and characterize abnormalities of the nervous system holds immense clinical relevance. Accurate diagnosis is paramount for implementing timely and effective therapeutic interventions, which may include pharmacotherapy, surgical procedures, physical therapy, or other rehabilitative strategies. Early detection, often facilitated by genetic screening or advanced neuroimaging, can significantly alter the disease trajectory, improve patient prognosis, and enhance their overall quality of life. Furthermore, understanding the genetic basis of these conditions paves the way for personalized medicine, enabling the development of targeted prevention strategies and novel therapies that are tailored to an individual’s unique genetic profile. Ongoing research, such as the identification of genetic risk loci, is fundamental for advancing diagnostic tools and discovering new therapeutic targets.

Social Importance

Nervous system abnormalities pose a significant global public health challenge, affecting millions worldwide and placing substantial burdens on healthcare systems and national economies. Beyond the direct medical costs, these conditions frequently lead to chronic disability, diminished productivity, and a profound impact on the quality of life for affected individuals and their caregivers. The social importance of addressing these abnormalities extends to fostering greater public awareness, reducing the pervasive stigma associated with neurological and psychiatric disorders, and ensuring robust support systems for patients and their families. Continued investment in research aimed at unraveling the genetic and environmental factors contributing to these conditions is essential for developing effective prevention strategies, improving treatments, and ultimately mitigating the widespread societal impact of nervous system disorders.

Limitations

Methodological and Statistical Considerations

Many genetic association studies, while robustly designed, face inherent methodological limitations. Sample sizes, even when large, may still be insufficient to detect variants with small effect sizes or to fully resolve complex genetic architectures, leading to potential underestimation of the full genetic contribution ^[6]. The stringent statistical thresholds, such as a genome-wide significance level of P < 5 × 10−8 or applying Bonferroni correction, are crucial for minimizing false positives given the vast number of SNPs tested, but they can also obscure true associations that fall just below these thresholds ^[7]. Furthermore, while efforts are made to ensure population homogeneity and adjust for principal components to mitigate stratification ^[8], subtle cohort biases or unmeasured confounders can still influence observed associations and their interpretation.

Phenotypic Complexity and Generalizability

A significant challenge lies in the precise definition and consistent measurement of abnormality of the nervous system, which encompasses a wide spectrum of conditions from specific disorders like glioma or myasthenia gravis to broader complaints like insomnia or refractive errors^[1]. The heterogeneity within these phenotypes can obscure underlying genetic signals or lead to inconsistent findings across studies. Moreover, the generalizability of findings is often limited by the specific ancestral cohorts studied, such as those focusing solely on South Asian populations or predominantly European-ancestry cohorts ^[6]. While multi-ancestry meta-analyses are increasingly employed to enhance power and broaden applicability ^[9], comprehensive representation of global genetic diversity remains a challenge, potentially limiting the translation of findings to diverse populations.

Holistic Etiology and Knowledge Gaps

Genetic association studies primarily identify genetic loci, but they often do not fully capture the complex interplay between genetic predispositions and environmental factors that contribute to the manifestation of nervous system abnormalities. Lifestyle, diet, exposure to toxins, and other environmental influences can significantly modify genetic risk, and the current studies provide limited insight into these gene-environment interactions. This complexity contributes to the phenomenon of “missing heritability,” where identified genetic variants explain only a fraction of the total heritable risk for a given trait. Consequently, despite the identification of numerous susceptibility loci, substantial knowledge gaps persist regarding the complete etiological pathways and the precise biological mechanisms through which these genetic variants contribute to nervous system abnormalities, underscoring the need for further integrative research.

Variants

The genetic landscape of neurological health and disease is complex, with numerous genes and their variants playing intricate roles. Among these, variants inSLC24A3, PALLD, and the ZSCAN16 locus are gaining attention for their potential influence on nervous system function and susceptibility to related abnormalities. These genes contribute to fundamental cellular processes, and even subtle alterations can have widespread effects on neuronal development, signaling, and maintenance.

A variant of interest is rs6106107 , located within the SLC24A3 gene. SLC24A3encodes a member of the potassium-dependent sodium-calcium exchanger family (NCKX), which are integral membrane proteins critical for maintaining calcium homeostasis within cells. In neurons, precise regulation of intracellular calcium levels is paramount for processes such as neurotransmitter release, synaptic plasticity, and the generation of action potentials. The NCKX exchangers actively pump calcium out of the cell, preventing calcium overload that can lead to excitotoxicity and neuronal damage. While the specific impact ofrs6106107 on SLC24A3function is subject to ongoing research, variants in genes governing calcium dynamics can modulate neuronal excitability and resilience, potentially contributing to the risk or progression of neurological conditions characterized by altered calcium signaling, such as epilepsy, neurodegenerative diseases, or certain neurodevelopmental disorders.

Another significant variant, rs62334264 , is found within the PALLD gene, which codes for palladin, an actin-associated protein. Palladin plays a crucial role in organizing the actin cytoskeleton, a dynamic network essential for maintaining cell shape, facilitating cell migration, and enabling intracellular transport. In the nervous system, actin dynamics are fundamental for neurite outgrowth, the precise guidance of growth cones during development, the formation and maturation of synapses, and the ongoing structural plasticity that underlies learning and memory. Variations like rs62334264 could potentially influence the expression or function of palladin, thereby affecting the intricate architecture and dynamic reorganization of the neuronal cytoskeleton. Such alterations might impact synaptic strength, neuronal connectivity, or even contribute to the pathogenesis of conditions involving structural defects in neurons or dysfunctional synaptic transmission.

The locus encompassing ZSCAN16 and ZSCAN16-AS1 is associated with the variant rs960872412 . ZSCAN16 encodes a zinc finger protein, typically functioning as a transcription factor that regulates the expression of other genes. Transcription factors are essential for controlling gene networks involved in neuronal differentiation, development, and the maintenance of mature neuronal function. ZSCAN16-AS1 is an antisense long non-coding RNA (lncRNA) transcribed from the opposite strand of ZSCAN16. LncRNAs are increasingly recognized as vital regulators of gene expression, influencing everything from chromatin structure to mRNA stability. The interplay between ZSCAN16 and its antisense lncRNA ZSCAN16-AS1 suggests a finely tuned regulatory mechanism at this genomic locus. A variant like rs960872412 could disrupt this delicate balance, altering the expression levels or activity of either the protein-coding gene or the lncRNA. This could lead to downstream effects on numerous target genes, potentially impacting critical processes in brain development, neuronal plasticity, or cellular stress responses, thereby contributing to the susceptibility to various neurological or neuropsychiatric disorders.

Key Variants

RS ID	Gene	Related Traits
rs6106107	SLC24A3	abnormality of the nervous system
rs62334264	PALLD	abnormality of the nervous system
rs960872412	ZSCAN16, ZSCAN16-AS1	abnormality of the nervous system

Causes of Nervous System Abnormality

Abnormalities of the nervous system arise from a complex interplay of genetic predispositions, environmental factors, and developmental processes. These conditions can manifest in various forms, from structural anomalies to functional impairments, often involving multiple causal pathways. Research indicates that many nervous system abnormalities are not due to a single cause but rather a combination of inherited vulnerabilities and external influences.

Genetic Predisposition and Polygenic Risk

Genetic factors are fundamental to the development of many nervous system abnormalities, ranging from single-gene disorders to complex polygenic conditions. For instance, the risk for certain brain tumors like glioma is significantly influenced by genetic variants; specific susceptibility loci have been identified in regions such as CDKN2B and RTEL1 for high-grade glioma. ^[2] Variation on chromosome 7p11.2 (EGFR) also plays a role in glioma risk, with studies revealing five distinct susceptibility loci for the condition and specific genetic differences between glioblastoma and non-glioblastoma tumors. ^[10] Similarly, the autoimmune neuromuscular disorder myasthenia gravis has genetic underpinnings, with risk mapping to a particular change in TNIP1 and to human leukocyte antigen-B*08. ^[1]

Complex neurological traits, such as insomnia, also demonstrate a polygenic architecture, where multiple genes contribute to an individual’s susceptibility. Research has identified various risk genes for insomnia complaints, noting genetic overlap with psychiatric and metabolic disorders, as well as sex-specific genetic effects. ^[4]Myopia and refractive errors, though primarily affecting the eye, are also considered nervous system-related abnormalities due to the eye’s direct connection to the brain and its intricate neural development. These conditions are often polygenic, with segregation analyses indicating the involvement of multiple genes rather than a single major gene effect. Genome-wide association studies have pinpointed numerous susceptibility loci, including regions at 15q25, 15q14, and variants in RBFOX1, a gene that regulates tissue-specific splicing.^[7]

Environmental Triggers and Gene-Environment Interactions

While genetic predisposition lays the groundwork for vulnerability, environmental factors can act as crucial triggers or modifiers, particularly through gene-environment interactions. A clear example is seen in febrile seizures, a common neurological event in childhood. Research indicates that common genetic variants are associated with both general febrile seizures and those specifically related to the Measles, Mumps, and Rubella (MMR) vaccine. ^[3]This highlights how an environmental exposure, such as a vaccine, can interact with an individual’s genetic makeup to precipitate a nervous system abnormality. Understanding these interactions offers insights into mechanisms of epileptogenesis and neuronal hyperexcitability, suggesting that external factors can influence the expression of genetic predispositions, leading to clinical manifestations.

Developmental Influences and Regulatory Mechanisms

The precise development and functioning of the nervous system rely on intricate regulatory mechanisms, and disruptions in these processes can lead to abnormalities. The insights gained from studying conditions like febrile seizures, which involve mechanisms of epileptogenesis and neuronal hyperexcitability, underscore the importance of proper neuronal development and circuit formation. ^[3] Similarly, the identification of variants in RBFOX1, a gene crucial for tissue-specific splicing, in the context of refractive error, points to the critical role of gene regulation during development. ^[11] Accurate gene expression and splicing are essential for the formation and maintenance of neural structures and functions, and any perturbation can contribute to the emergence of nervous system abnormalities.

Comorbidities and Interacting Health Conditions

The presence of other health conditions, or comorbidities, can significantly contribute to or exacerbate nervous system abnormalities. This interconnectedness is particularly evident in complex traits such as insomnia. Genetic analyses have revealed significant genetic overlap between insomnia complaints and several psychiatric and metabolic disorders. ^[4] This suggests that the genetic pathways contributing to insomnia may also be involved in other health issues, creating a complex web of interacting conditions. The presence of these psychiatric or metabolic comorbidities can therefore influence the manifestation, severity, or progression of nervous system abnormalities, highlighting the importance of a holistic view in understanding their causes.

Biological Background

The nervous system is a complex network responsible for controlling and coordinating all bodily functions, including thought, movement, and sensation. Abnormality of the nervous system encompasses a wide range of conditions resulting from disruptions in its structure, function, or development. These abnormalities can stem from intricate interactions between genetic predispositions, cellular dysregulation, and environmental factors, leading to diverse neurological disorders.

Genetic Predisposition and Regulatory Mechanisms

Genetic factors play a significant role in determining an individual’s susceptibility to various nervous system abnormalities. Common genetic variants have been identified that are associated with an increased risk for conditions such as febrile seizures, which involve episodes of neuronal hyperexcitability, and insomnia complaints, indicating a genetic basis for sleep regulation disturbances s of chromosomes; variants in these genes can impair normal telomere function, contributing to the genomic instability characteristic of high-grade gliomas These genetic predispositions suggest alterations in developmental pathways crucial for ocular and neural integrity. Similarly, insomnia complaints are linked to identified risk genes, indicating that inherited factors can perturb the complex neural circuits governing sleep-wake cycles. ^[4]

In more severe nervous system disorders, such as glioma, genetic variants in regions like CDKN2B and RTEL1, along with variations in EGFR, are associated with increased disease risk.^[2] These genes are integral to cell cycle control, DNA repair, and growth factor signaling, where their dysregulation can lead to uncontrolled proliferation of neural cells. Furthermore, the risk for myasthenia gravis is linked to a specific change in TNIP1 and to HLA-B*08, demonstrating how genetic variations in immune regulatory pathways can aberrantly impact the neuromuscular junction, disrupting crucial nervous system communication. ^[1]

Signaling Pathways in Neuronal Homeostasis and Dysregulation

Signaling pathways are central to the precise communication and functional integrity of the nervous system, with their dysregulation contributing to various abnormalities. The mechanisms underlying epileptogenesis and neuronal hyperexcitability, as observed in common variants associated with febrile seizures, involve perturbations in the delicate balance of neuronal firing. ^[3] This can stem from altered receptor activation dynamics, modifications to ion channel function, or disruptions within intracellular signaling cascades that normally maintain synaptic homeostasis. Such imbalances can lead to uncontrolled electrical activity and neuronal network instability.

In the context of glioma, variations in the Epidermal Growth Factor Receptor (EGFR) region influence disease risk, highlighting the critical role of receptor activation in neural cell proliferation and survival.^[10]Aberrant EGFR signaling can drive constitutive activation of downstream cascades, overriding normal cellular feedback loops and promoting unchecked cell growth. Furthermore, in myasthenia gravis, the immune system’s attack on acetylcholine receptors at the neuromuscular junction directly impairs neurotransmission, representing a critical breakdown in signaling between nerve and muscle, ultimately leading to functional nervous system abnormality.^[1]

Metabolic and Cellular Maintenance Pathways

The nervous system relies heavily on robust metabolic and cellular maintenance pathways to sustain its high energy demands and complex cellular architecture. Dysregulation in these pathways can manifest as various abnormalities, such as in glioma, where variants near TERT and TERC are associated with altered telomere length and increased disease risk.^[12]These findings underscore the critical importance of DNA maintenance and cellular aging mechanisms in controlling cell proliferation and preventing malignant transformation within neural tissues. The proper functioning of biosynthesis and catabolism is paramount for neuronal health and integrity.

Furthermore, the observation of genetic overlap between insomnia complaints and metabolic traits suggests that disruptions in energy metabolism or related regulatory pathways may contribute to sleep disturbances. ^[4]Neuronal activity is energetically intensive, requiring precise metabolic regulation and flux control to ensure adequate ATP supply and neurotransmitter synthesis. Protein modification and post-translational regulation also play crucial roles, ensuring the correct folding, localization, and activity of proteins involved in neural signaling and structural integrity, with any disruption potentially leading to functional impairment.

Systems-Level Integration and Disease Emergence

Abnormalities of the nervous system often emerge from the intricate interplay and crosstalk between multiple molecular pathways, extending beyond single gene effects to complex network interactions. For instance, the genetic overlap identified between insomnia complaints and both psychiatric and metabolic traits highlights how dysregulation in one system can propagate and influence others, leading to a broader systemic impact on neural function. ^[4]This emphasizes the hierarchical regulation within biological systems, where disruptions at various levels can contribute to emergent properties of disease phenotypes.

Understanding such systems-level integration is crucial for deciphering the pathogenesis of conditions like epileptogenesis and neuronal hyperexcitability, where complex network-level dysregulation, rather than a single pathway defect, often drives the pathology. ^[3]The nervous system’s capacity for compensatory mechanisms can initially buffer against minor perturbations, but persistent or severe pathway dysregulation can overwhelm these safeguards, leading to overt disease. Identifying these critical nodes and points of crosstalk offers potential avenues for developing therapeutic targets that can restore network balance and mitigate disease progression.

Clinical Relevance

Genetic insights into abnormalities of the nervous system offer crucial clinical relevance across various stages of patient care, from risk assessment to treatment optimization. Understanding the genetic underpinnings of these conditions can lead to more precise diagnostics, personalized medicine approaches, and a clearer understanding of disease trajectories and associated health challenges.

Genetic Risk and Early Identification

Genetic studies have identified specific loci associated with an increased risk for several nervous system abnormalities, enabling improved risk stratification and the potential for early identification of high-risk individuals. For instance, variants near TERT and TERC have been linked to an elevated risk of high-grade glioma, while variations in CDKN2B, RTEL1, EGFR, and loci on chromosomes 1 and 9 also influence overall glioma susceptibility ^[12]. Furthermore, research differentiates genetic susceptibility between glioblastoma and non-glioblastoma tumors, suggesting distinct underlying mechanisms that could inform subtype-specific risk assessment ^[13]. In multiple system atrophy (MSA), genome-wide association studies have begun to uncover genetic predispositions, providing avenues for early identification of individuals at higher risk for this progressive neurodegenerative disorder ^[5]. Similarly, specific genetic markers, such as a Pro→Ala change in TNIP1 and the HLA-B08 allele, are associated with an increased risk for myasthenia gravis, potentially aiding in identifying susceptible individuals before symptom onset or guiding early diagnostic pathways ^[1]. Common genetic variants have also been identified for febrile seizures, offering insights into general mechanisms of epileptogenesis and neuronal hyperexcitability, which could contribute to risk stratification for recurrent seizures or related neurological conditions ^[3].

Prognosis, Treatment Selection, and Monitoring

Genetic insights into nervous system disorders can inform prognostic predictions, personalize treatment strategies, and guide monitoring approaches. For example, understanding the specific genetic susceptibility of glioma subtypes, such as glioblastoma versus non-glioblastoma, may allow for more accurate prognostication regarding disease progression and potential response to targeted therapies^[13]. The identification of variants influencing telomere length, like those near TERT and TERC, associated with high-grade glioma risk, could also have prognostic implications, as telomere dynamics are linked to cellular aging and tumor aggressiveness^[12]. In autoimmune conditions like myasthenia gravis, genetic associations, particularly with HLA-B08, may not only indicate susceptibility but also influence disease phenotype or response to immunomodulatory treatments, guiding personalized therapeutic approaches^[1]. For conditions such as multiple system atrophy, identifying genetic markers could eventually lead to the development of monitoring strategies to track disease progression or evaluate the efficacy of novel interventions^[5]. This genetic information, when integrated with clinical data, can refine risk assessment, enabling clinicians to select optimal treatments and tailor long-term management plans for individual patients ^[13].

Comorbidity and Overlapping Phenotypes

Genetic studies reveal significant overlap between nervous system abnormalities and other health conditions, highlighting shared biological pathways and potential comorbidities. For example, genome-wide association analyses of insomnia complaints have identified risk genes that also show genetic overlap with psychiatric and metabolic traits ^[4]. This suggests that individuals with a genetic predisposition to insomnia may also be at an increased risk for certain mental health disorders or metabolic dysregulation, necessitating a holistic approach to patient care that considers these interconnected health aspects ^[4]. Furthermore, the identification of common variants linked to febrile seizures provides insights into general mechanisms of epileptogenesis and neuronal hyperexcitability, which could potentially overlap with other seizure disorders or conditions characterized by altered neuronal excitability ^[3]. Recognizing these genetic associations and overlapping phenotypes is crucial for comprehensive risk assessment, early detection of comorbid conditions, and developing integrated prevention and management strategies that address the full spectrum of a patient’s health ^[4].

Frequently Asked Questions About Abnormality Of The Nervous System

These questions address the most important and specific aspects of abnormality of the nervous system based on current genetic research.

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1. My family has a history of brain issues. Will I get them too?

Not necessarily. While genetic factors play a significant role, having a family history means you might have a higher predisposition, but it’s not a guarantee. Many nervous system conditions arise from a complex mix of your genes, environment, and developmental processes, not just one factor. Understanding your family’s specific conditions can help guide discussions with your doctor.

2. Should I get a genetic test if I worry about my brain health?

Genetic testing can be a powerful tool for understanding your risk for certain conditions. For some disorders, specific genetic markers are known, and identifying them can help with early detection and personalized prevention strategies. However, it’s best to discuss this with a healthcare professional to see if it’s appropriate for your situation, as not all risks are solely genetic.

3. Can a DNA test tell me if I’ll get a brain tumor?

For some types of brain tumors, like glioma, researchers have identified several genetic susceptibility loci across different chromosomes that increase risk. A DNA test could reveal if you carry some of these common genetic variations. This information doesn’t mean you will get a tumor, but it can provide insights into your individual predisposition, allowing for informed discussions with your doctor about monitoring.

4. Why do some people get nervous system problems early, and others much later?

The timing of onset can be influenced by the specific genetic predispositions a person carries, how strongly those genes are expressed, and their lifetime environmental exposures. Some conditions have clearer genetic links that might manifest earlier, while others are more multifactorial and develop over time with accumulated risk factors.

5. Does my sleep affect my risk for brain problems later?

Yes, research has shown a connection. Studies have identified specific risk genes for insomnia, and these genes also show genetic overlap with psychiatric and metabolic traits. This suggests that sleep patterns and their genetic underpinnings can be part of the broader picture of nervous system health and susceptibility to certain conditions.

6. Can I prevent nervous system issues even with a ‘bad’ family history?

While genetics play a role in susceptibility, they don’t determine everything. Early detection and timely interventions, including pharmacotherapy, physical therapy, or other rehabilitative strategies, can significantly alter the disease trajectory and improve your prognosis. Understanding your genetic predispositions can help you and your doctor develop targeted prevention strategies.

7. Why are some nervous system problems more common in certain groups?

The prevalence of certain conditions can vary across different populations due to a combination of genetic and environmental factors. Genetic studies often focus on specific ancestral groups, and genetic risk factors can differ between these groups, leading to varying susceptibilities. This highlights the importance of diverse research cohorts.

8. If my brain feels ‘off,’ is it just stress or something real?

It’s important to take any persistent changes in cognitive abilities, motor control, sensory perception, or emotional regulation seriously. While stress can impact well-being, these symptoms could also indicate a deviation from typical nervous system function. Accurate diagnosis is paramount for understanding the cause and implementing effective therapeutic interventions.

9. Why do some of my relatives get a nervous system issue, but others don’t?

Even within families, there’s genetic variation, and individuals have different environmental exposures. While some family members might inherit common genetic variations that increase susceptibility, others might not, or they might experience different environmental triggers. It’s a complex interplay of many factors that influences who develops a condition.

10. Does something like having a high fever as a kid affect my brain risk?

Yes, for some conditions. For example, common genetic variants have been linked to an increased risk for febrile seizures, which are seizures triggered by a high fever in childhood. This highlights how specific genetic predispositions can interact with environmental events to influence nervous system health and susceptibility to certain conditions.

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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

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[2] Wrensch, M et al. “Variants in the CDKN2B and RTEL1 regions are associated with high-grade glioma susceptibility.” Nature Genetics, 2009, PMID: 19578366.

[3] Feenstra, B. et al. “Common variants associated with general and MMR vaccine-related febrile seizures.” Nat Genet, vol. 46, no. 12, 2014, pp. 1274-1282.

[4] Hammerschlag, A. R. et al. “Genome-wide association analysis of insomnia complaints identifies risk genes and genetic overlap with psychiatric and metabolic traits.” Nat Genet, vol. 49, no. 9, 2017, pp. 1383-1388.

[5] Sailer, A., et al. “A genome-wide association study in multiple system atrophy.” Neurology, 2016.

[6] Stokowski, RP. “A genomewide association study of skin pigmentation in a South Asian population.” American Journal of Human Genetics, December 2007, PMID: 17999355.

[7] Solouki, A. M. et al. “A genome-wide association study identifies a susceptibility locus for refractive errors and myopia at 15q14.”Nat Genet, vol. 42, no. 10, 2010, pp. 892-895.

[8] Hysi, P. G. et al. “A genome-wide association study for myopia and refractive error identifies a susceptibility locus at 15q25.”Nat Genet, vol. 42, no. 10, 2010, pp. 896-899.

[9] Verhoeven, V. J. et al. “Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia.”Nat Genet, vol. 45, no. 3, 2013, pp. 314-318.

[10] Sanson, M. et al. “Chromosome 7p11.2 (EGFR) variation influences glioma risk.” Hum Mol Genet, vol. 20, no. 14, 2011, pp. 2829-2836.

[11] Stambolian, D. et al. “Meta-analysis of genome-wide association studies in five cohorts reveals common variants in RBFOX1, a regulator of tissue-specific splicing, associated with refractive error.” Hum Mol Genet, vol. 22, no. 10, 2013, pp. 2116-2126.

[12] Walsh, K. M., et al. “Variants near TERT and TERC influencing telomere length are associated with high-grade glioma risk.” Nat Genet., vol. 46, no. 7, Jul. 2014, pp. 731-5.

[13] Melin, B. S. et al. “Genome-wide association study of glioma subtypes identifies specific differences in genetic susceptibility to glioblastoma and non-glioblastoma tumors.” Nat Genet, vol. 49, no. 5, 2017, pp. 789-794.