Nervous System Disease

Nervous system diseases encompass a broad category of conditions that affect the brain, spinal cord, and the intricate network of nerves throughout the body. These disorders can disrupt the body’s ability to function, impacting movement, sensation, cognition, and overall quality of life. Understanding these conditions is crucial due to their significant burden on individuals and healthcare systems worldwide.

The biological basis of nervous system diseases is complex, often involving a combination of genetic predispositions, environmental factors, and lifestyle influences. The nervous system relies on intricate communication between neurons, and disruptions at various levels—from genetic mutations affecting protein function to inflammation, trauma, or neurodegeneration—can lead to disease. For instance, genetic research, including genome-wide association studies (GWAS), has identified specific genetic variants associated with an increased risk for conditions such as Alzheimer’s disease^[1], ^[2], ^[3], Parkinson’s disease^[4], and various forms of glioma ^[5], ^[6]. These studies highlight the role of inherited factors in susceptibility to these disorders, pointing towards pathways involved in neuronal health, immune response, and cellular maintenance.

Clinically, nervous system diseases manifest in a wide range of symptoms, from subtle cognitive changes and motor difficulties to severe paralysis and dementia. Diagnosis often involves a combination of neurological examination, imaging techniques, and genetic testing. While many nervous system diseases currently lack a cure, advancements in treatment focus on managing symptoms, slowing disease progression, and improving patients’ functional abilities through medications, physical therapy, and other interventions.

The social importance of addressing nervous system diseases is profound. They represent a leading cause of disability and mortality globally, placing substantial demands on long-term care, family caregivers, and public health resources. Continued research into their causes, particularly genetic factors, holds the promise of developing more effective diagnostic tools, preventative strategies, and targeted therapies, ultimately aiming to alleviate suffering and improve the lives of millions affected by these debilitating conditions.

Limitations

Methodological and Statistical Considerations

Research into nervous system diseases, particularly through genome-wide association studies (GWAS), is subject to several methodological and statistical constraints. A fundamental limitation is the necessity for replication studies to confirm associations identified in initial GWAS ^[7]. While very low P values (e.g., P<5×10-7) in large sample sizes provide strong evidence, subsequent replication is crucial to validate findings and further delineate the range of associated phenotypes and functionally relevant variations ^[7]. Moreover, the failure to detect a prominent association signal in a study does not conclusively rule out a gene, as current genotyping arrays may offer incomplete coverage of common genomic variation and typically provide poor coverage of rare or structural variants, thereby limiting the power to identify such alleles ^[7].

Interpreting the significance levels in genome-wide studies demands careful consideration of corrections for multiple comparisons, a critical aspect given the vast number of statistical tests performed ^[7]. The effect sizes of individual genetic variants identified are often modest, and associations established within specific cohorts may not be immediately generalizable without further validation. These challenges underscore the ongoing need for robust study designs and rigorous statistical approaches to differentiate genuine biological signals from potential statistical artifacts.

Population Heterogeneity and Phenotypic Complexity

The generalizability of findings in nervous system disease research can be constrained by population structure and phenotypic complexity. Apparent genetic associations may sometimes be confounded by underlying geographical or ancestral differentiation within study populations^[7]. Although analyses often suggest a minimal confounding effect from population structure, caution is warranted when interpreting associations in genomic regions known to exhibit strong geographical differentiation ^[7]. Additionally, the inherent variability in defining and measuring complex phenotypes across different studies can introduce heterogeneity, and it is recognized that genetic effects may manifest differently between males and females, necessitating sex-specific analyses to fully understand disease mechanisms^[7].

The broad classification of “nervous system disease” encompasses a multitude of distinct conditions, each potentially characterized by its own unique genetic architecture. The transferability of genetic insights from one specific disease cohort to a broader patient population is often limited by these precise phenotypic distinctions and the specific diagnostic criteria employed for case ascertainment. Therefore, careful consideration of population demographics and detailed phenotypic characterization are essential for accurate interpretation and broader applicability of research findings.

Unexplained Heritability and Translational Gaps

Despite significant advancements in identifying susceptibility loci for nervous system diseases through GWAS, a substantial proportion of the heritability for many complex conditions remains unexplained, a phenomenon often referred to as “missing heritability” ^[7]. This suggests that numerous additional susceptibility effects are yet to be discovered, potentially involving rarer genetic variants, complex structural variations, or intricate gene-gene and gene-environment interactions that are not fully captured by current research methodologies ^[7]. Further research is imperative to uncover these hidden genetic components and to understand their interplay with environmental factors.

While genetic associations provide valuable insights into the biological pathways implicated in nervous system diseases, the identified loci, whether considered individually or in combination, have not yet provided clinically useful prediction of disease^[7]. Bridging this gap between genetic discovery and clinical utility requires extensive efforts to thoroughly characterize pathologically relevant genetic variations and to translate these findings into practical applications such as improved diagnostic tools, prognostic indicators, or novel therapeutic targets. The ultimate goal remains to leverage genetic knowledge for enhanced patient care, a goal that necessitates continued research and development.

Variants

Genetic variations play a crucial role in influencing an individual’s susceptibility to various nervous system diseases. These variants can affect gene function, protein structure, and cellular pathways essential for brain development, maintenance, and communication. Understanding these genetic contributions helps to unravel the complex etiology of neurological disorders.

The apolipoprotein E gene,APOE, is a well-established genetic risk factor for late-onset Alzheimer’s disease (AD). Thers429358 variant, specifically the APOE ε4 allele, is a major determinant of AD susceptibility ^[8]. This allele leads to a protein isoform that is less efficient at clearing amyloid-beta peptides from the brain and may promote their aggregation into neurotoxic plaques, a hallmark of AD pathology. Studies have consistently shown that individuals carrying the APOE ε4 allele have a significantly increased risk of developing Alzheimer’s disease, with a high odds ratio compared to those with other APOE genotypes^[9]. The profound impact of APOE on AD risk has often led researchers to account for or remove APOE-linked variants in genome-wide association studies to identify additional, independent AD susceptibility loci ^[1].

Other variants impact genes crucial for neuronal signaling and synaptic integrity. The GRIK2gene encodes a subunit of kainate receptors, which are vital components of glutamate receptors mediating excitatory neurotransmission in the brain. Variants such asrs139339493 in GRIK2can affect receptor function, potentially altering neuronal excitability and synaptic plasticity, processes implicated in epilepsy and neurodegenerative conditions. Similarly,NXPH1 (Neurexophilin 1) produces a protein that interacts with neurexins, essential cell adhesion molecules for synapse formation and stability. The rs763082055 variant in NXPH1 could therefore impact synaptic organization, which is fundamental to the pathogenesis of many nervous system disorders. FARP1 (FERM, ARHGEF And Pleckstrin Domain Protein 1) is involved in regulating the actin cytoskeleton, crucial for neuronal morphology and connectivity. The rs9584835 variant in FARP1might alter these processes, contributing to neurodevelopmental or neurodegenerative traits, as disruptions in neuronal structure are often observed in conditions like Alzheimer’s disease^[8]. Genome-wide association studies continue to reveal the diverse genetic landscape underlying the complex inheritance of late-onset Alzheimer’s disease, highlighting the multifactorial nature of such conditions^[9].

Further variants affect genes with broader roles in cellular regulation and development, which are nonetheless critical for nervous system health. CAMTA1 (Calmodulin-Binding Transcription Activator 1) encodes a transcription factor that regulates gene expression in response to calcium signals, key for neuronal activity and plasticity. The rs143552363 variant could alter CAMTA1’s regulatory functions, impacting genes vital for neuronal development and survival. GPC6 (Glypican 6) is a cell surface proteoglycan involved in growth factor signaling and cell-cell interactions during development. A variant like rs2150127 in GPC6 might influence processes like neurogenesis or axon guidance, potentially contributing to developmental brain anomalies. The CDC5L and SUPT3H genes are involved in essential cellular processes like RNA splicing and transcriptional regulation, respectively. The rs9367197 variant affecting these genes could have widespread consequences for protein synthesis and overall neuronal function. HHAT (Hedgehog Acyltransferase) is integral to the Hedgehog signaling pathway, a pathway crucial for central nervous system embryonic development. The rs536642077 variant might modify HHAT activity, impacting brain patterning. NOPCHAP1 (Nucleolar Protein Containing CHAP Domain 1) is a nucleolar protein likely involved in ribosome biogenesis, essential for protein production in neurons. A variant like rs146329438 could impair this function, contributing to neurodegeneration. Finally, PTGFR (Prostaglandin F Receptor) encodes a receptor for prostaglandin F2-alpha, a lipid mediator involved in inflammation and neuronal activity. The rs183356941 variant in PTGFR could influence neuroinflammatory responses or neuronal excitability, potentially impacting neuroinflammatory diseases ^[1]. These genetic insights underscore the intricate interplay of various cellular pathways in the development and progression of complex neurological conditions ^[2].

Key Variants

RS ID	Gene	Related Traits
rs429358	APOE	cerebral amyloid deposition measurement Lewy body dementia, Lewy body dementia measurement high density lipoprotein cholesterol measurement platelet count neuroimaging measurement
rs536642077	HHAT	nervous system disease
rs763082055	NXPH1 - GAPDHP68	nervous system disease
rs183356941	PTGFR, MGC27382	nervous system disease
rs9367197	CDC5L - SUPT3H	nervous system disease
rs143552363	CAMTA1-IT1, CAMTA1	nervous system disease
rs2150127	GPC6	nervous system disease
rs146329438	NOPCHAP1	nervous system disease
rs9584835	FARP1	nervous system disease
rs139339493	GRIK2 - R3HDM2P2	nervous system disease

Classification, Definition, and Terminology

Defining Neurological Conditions and Associated Traits

Nervous system diseases, such as Alzheimer’s disease, Parkinson’s disease, and high-grade glioma, are recognized as distinct clinical entities that are subject to detailed genetic investigation . For instance, specific alleles of theGAB2gene have been found to modify the risk of Alzheimer’s disease, particularly in individuals who carry theAPOE ε4allele, demonstrating gene-gene interactions that influence disease susceptibility^[3]. Furthermore, research has identified a significant risk locus on chromosome 12 for late-onset Alzheimer’s disease, highlighting specific genomic regions involved in disease etiology^[1]. Similarly, familial forms of Parkinson disease are linked to specific susceptibility genes^[4], and several distinct loci have been associated with an increased risk for glioma, including variants in the CDKN2B and RTEL1 regions, underscoring the genetic heterogeneity underlying these conditions ^[5].

Gene-Environment Interactions

While genetic factors provide a foundation for susceptibility, environmental elements often act as crucial triggers or modulators, leading to the manifestation of nervous system diseases through gene-environment interactions. These interactions describe how an individual’s genetic predisposition can be amplified or mitigated by exposure to various external factors, including lifestyle choices, dietary habits, and specific environmental exposures. Although the precise mechanisms for many nervous system diseases are still being elucidated, it is understood that an individual carrying a genetic risk variant may only develop the disease if exposed to particular environmental conditions, or conversely, protective environmental factors might prevent disease onset even in genetically predisposed individuals. The interplay between an individual’s unique genetic makeup and their environment therefore significantly shapes their overall risk profile for developing nervous system disorders.

Age-Related Factors

Advancing age is a predominant risk factor for many nervous system diseases, with physiological changes over the lifespan significantly impacting neurological health. The accumulation of cellular damage, oxidative stress, and impaired repair mechanisms associated with aging can render the nervous system more vulnerable to disease^[1]. For neurodegenerative conditions such as late-onset Alzheimer’s disease, age is the most significant non-genetic risk factor, with the incidence dramatically increasing in older populations^[1]. These age-related changes can interact with existing genetic predispositions, accelerating disease progression or lowering the threshold for environmental triggers to initiate pathological processes.

Biological Background of Nervous System Disease

Nervous system diseases encompass a broad range of conditions that affect the brain, spinal cord, and nerves throughout the body. These disorders can arise from a complex interplay of genetic predispositions, molecular dysfunctions, and environmental factors, leading to diverse clinical manifestations from neurodegeneration to abnormal cellular proliferation. Understanding the underlying biological mechanisms is crucial for developing effective diagnostic tools and therapeutic interventions.

Genetic Architecture of Nervous System Diseases

Genetic studies, particularly genome-wide association studies (GWAS), have been instrumental in uncovering the complex genetic landscape underlying various nervous system diseases. These studies identify specific genetic variants, or loci, that are associated with an increased susceptibility to developing these conditions. For instance, alleles of the GAB2gene have been found to modify the risk of Alzheimer’s disease, particularly in individuals who carry theAPOE epsilon4allele, highlighting gene-gene interactions in disease susceptibility^[3]. Further research has pinpointed a risk locus on chromosome 12 specifically for late-onset Alzheimer’s disease, suggesting multiple genetic contributors to this common neurodegenerative disorder^[1]. Similarly, susceptibility genes contributing to familial Parkinson’s disease have been identified through genomewide association analyses, indicating a hereditary component in some forms of this movement disorder^[4]. For brain cancers such as high-grade glioma, variants within the CDKN2B and RTEL1 regions are associated with increased susceptibility, implicating these genes in cellular growth control and DNA repair pathways relevant to tumor development ^[5].

Molecular and Cellular Dysregulation in Neurological Disorders

The genetic variants identified in nervous system diseases often point to disruptions in critical molecular and cellular pathways that maintain neuronal health and function. For example, the GAB2gene, implicated in Alzheimer’s risk, is known to play a role in intracellular signaling cascades, suggesting that alterations in these pathways contribute to disease pathogenesis^[3]. Such molecular dysregulation can impact cellular functions vital for neuronal survival and synaptic plasticity, leading to progressive neurodegeneration. Beyond specific gene functions, broader cellular processes are often compromised in neurological disorders. A common characteristic of several neurodegenerative conditions, collectively termed tauopathies, involves the abnormal accumulation and aggregation of tau protein, a key structural component of neurons ^[4]. While the precise mechanisms by which genetic variants like those in Parkinson’s disease or Alzheimer’s directly initiate tauopathy are complex, these findings underscore how genetic predispositions can perturb regulatory networks and metabolic processes, ultimately leading to protein misfolding and cellular toxicity across different nervous system pathologies.

Pathophysiology and Tissue-Level Impact

The interplay of genetic predispositions and molecular dysregulation culminates in distinct pathophysiological processes that define nervous system diseases, manifesting as specific tissue and organ-level effects. In Alzheimer’s disease, the genetic modifications involvingGAB2 and APOE epsilon4contribute to the accumulation of pathological hallmarks within brain tissue, disrupting neuronal networks and leading to cognitive decline^[3]. This disruption represents a failure of homeostatic mechanisms responsible for maintaining brain function and integrity. Similarly, the susceptibility genes identified for familial Parkinson’s disease are believed to contribute to the selective degeneration of dopaminergic neurons in specific brain regions, leading to the characteristic motor symptoms of the disease^[4]. In the context of high-grade glioma, variants in CDKN2B and RTEL1 are linked to uncontrolled cell proliferation and impaired DNA repair, resulting in aggressive tumor growth within brain tissue ^[5]. These examples illustrate how genetic factors initiate or exacerbate disease mechanisms, leading to profound and often irreversible damage to the central nervous system, impacting systemic neurological function.

Pathways and Mechanisms

Genetic Basis and Gene Regulatory Mechanisms

Genetic variations play a significant role in modulating an individual’s susceptibility to nervous system diseases. For instance, specific GAB2 alleles are recognized to modify the risk of Alzheimer’s disease, particularly interacting with the APOE epsilon4 genotype^[3]. Other genomic regions, such as a locus on chromosome 12, have also been identified as risk factors for late-onset Alzheimer disease^[1]. Similarly, studies have pinpointed susceptibility genes contributing to familial Parkinson disease^[4], and variants within the CDKN2B and RTEL1 regions are associated with an increased risk for high-grade glioma ^[5]. These genetic findings highlight how inherited differences can alter gene expression or protein function, thereby influencing the onset and progression of neurological disorders through regulatory mechanisms. These regulatory shifts can impact crucial cellular processes, ultimately contributing to disease pathogenesis.

Intracellular Signaling and Protein Homeostasis

The proper functioning of the nervous system relies on intricate intracellular signaling pathways, which can be disrupted in disease states. Genes like GAB2, implicated in Alzheimer’s disease, likely participate in complex signaling cascades involving receptor activation and subsequent intracellular responses^[3]. These cascades often regulate neuronal survival, synaptic plasticity, and cellular stress responses. Furthermore, post-translational regulation, including various protein modifications, is crucial for maintaining protein homeostasis. In neurodegenerative conditions such as tauopathies, which are relevant to Parkinson’s disease, abnormal modifications of proteins like tau lead to their misfolding and aggregation^[4]. This dysregulation of protein dynamics can overwhelm cellular catabolic processes, contributing to the formation of neurotoxic aggregates and the progressive loss of neuronal function.

Systems-Level Integration and Disease Pathogenesis

Nervous system diseases often arise from complex interactions across multiple biological pathways rather than isolated defects. The interplay between different genetic risk factors, such as the combined influence of GAB2 alleles and APOE epsilon4 in Alzheimer’s disease, exemplifies how pathway crosstalk can contribute to the overall disease phenotype^[3]. These network interactions involve hierarchical regulation, where alterations at one level can trigger cascading effects throughout the cellular system, leading to emergent properties like neuroinflammation or synaptic dysfunction. Understanding these broader network disruptions and their compensatory mechanisms is crucial for identifying effective therapeutic targets that address the systemic nature of neurological conditions. The collective breakdown of these interacting networks underscores the complexity of these disorders.

Risk Assessment and Early Identification

Genetic studies offer crucial insights into identifying individuals at higher risk for nervous system diseases, enabling proactive clinical strategies. For instance, specific genetic variants, such as GAB2 alleles, have been shown to modify Alzheimer’s risk, particularly in individuals who carry the APOE ε4 allele ^[3]. Such discoveries contribute to a personalized medicine approach by potentially allowing for early risk stratification and targeted interventions before symptom onset. Similarly, the identification of susceptibility genes for familial Parkinson’s disease through genome-wide association studies (GWAS) highlights their utility in identifying high-risk family members, paving the way for early monitoring and potentially preventative measures^[4].

Further, diagnostic utility is enhanced by identifying specific genetic loci associated with late-onset Alzheimer’s disease, such as a risk locus on chromosome 12 and variants atCLU and PICALM ^[1]. These genetic markers can complement traditional clinical assessments, offering a more precise risk profile for individuals. While current genetic markers may not provide clinically useful prediction for all common diseases when considered singly or in combination ^[7], their continuous discovery improves the precision of risk models and supports the development of tailored prevention strategies in specific patient populations.

Prognostic Insights and Disease Progression

Genetic findings also hold significant prognostic value, aiding in the prediction of disease outcomes and progression in nervous system disorders. For example, understanding the genetic landscape of Alzheimer’s disease, including variants likeCLU and PICALM, may offer clues about the trajectory of cognitive decline and the potential for long-term complications^[2]. Similarly, the identification of susceptibility genes in familial Parkinson’s disease could inform clinicians about the likely course of the disease, allowing for more informed discussions with patients and families regarding expectations and planning for future care^[4].

The response to treatment may also be influenced by an individual’s genetic makeup, although specific examples for nervous system diseases are not detailed in the provided context. However, the broader utility of genetic data in predicting outcomes and guiding treatment strategies is a rapidly evolving area. These insights are essential for developing monitoring strategies that are responsive to an individual’s predicted disease course, potentially leading to adjustments in medication, lifestyle interventions, or supportive therapies to optimize patient care and improve long-term implications.

Understanding Complexities and Comorbidities

The genetic underpinnings of nervous system diseases often reveal connections to other conditions and broader biological pathways, highlighting their complex nature. While studies primarily focus on direct genetic associations with conditions like Alzheimer’s and Parkinson’s, the broader investigation into genetic correlates of longevity and selected age-related phenotypes suggests potential overlaps between neurodegenerative processes and general aging pathways^[10]. This indicates that genetic factors influencing the aging process may also contribute to the risk or progression of nervous system disorders.

Moreover, genome-wide association studies across various diseases, such as coronary artery disease^[11]or inflammatory bowel disease^[12], demonstrate the potential for uncovering shared biological mechanisms or genetic predispositions that could lead to overlapping phenotypes or comorbidities, even if not directly neurological in origin. Although specific overlapping genetic risk factors or syndromic presentations for nervous system diseases are not extensively detailed in the provided context, the general principle of genetic studies identifying related conditions remains relevant. This comprehensive genetic understanding can ultimately lead to a more holistic view of patient health, informing clinicians about potential related conditions or complications to monitor for.

Frequently Asked Questions About Nervous System Disease

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

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1. My dad had Alzheimer’s; will I definitely get it too?

No, not necessarily. While genes play a significant role in conditions like Alzheimer’s, having variants in genes like APOE, CLU, PICALM, or GAB2 can increase your susceptibility, but it doesn’t mean you’ll definitely get it. It signifies a higher genetic predisposition, but environmental factors and lifestyle also heavily influence whether the disease develops.

2. Should I get a DNA test to check my brain health risk?

It depends on what you hope to learn. Genetic testing can identify specific variants, such as those in APOE, associated with an increased risk for some nervous system diseases like Alzheimer’s or Parkinson’s. However, these variants often have modest effect sizes, and current tests don’t fully capture all risk factors, meaning they haven’t yet provided clinically useful prediction for everyone.

3. Can I prevent a nervous system disease even if it runs in my family?

Yes, your lifestyle can definitely play a role. Nervous system diseases arise from a complex mix of genetic predispositions, environmental factors, and lifestyle choices. Even if you have a genetic susceptibility, managing your environment and adopting healthy habits can influence neuronal health and potentially modify your disease risk or progression.

4. My sibling has Parkinson’s, but I don’t. Why are we different?

There are many reasons for this. Even within families, genetic inheritance can vary, and you might have different combinations of risk-conferring genetic variants than your sibling. Additionally, environmental factors and lifestyle choices unique to each person can significantly influence who develops a disease, even with similar genetic backgrounds. Much of the genetic risk for complex conditions is still being discovered.

5. Does stress or poor sleep make genetic risks worse for my brain?

While the exact mechanisms are still being researched, environmental factors and lifestyle influences, including stress and sleep patterns, are known to interact with your genetic predispositions. Disruptions from inflammation or neurodegeneration can be influenced by these factors, potentially contributing to the development or progression of nervous system diseases in genetically susceptible individuals.

6. Does my family’s ethnic background change my risk for brain issues?

Yes, your ethnic background can influence your genetic risk profile. Research shows that genetic associations can sometimes be confounded by underlying geographical or ancestral differences within study populations. Different populations may have unique genetic architectures or varying frequencies of specific risk variants, which is why considering population demographics is important in research.

7. Does my risk for nervous system problems increase just because I’m getting older?

Yes, age is a significant risk factor for many nervous system diseases, particularly neurodegenerative conditions like Alzheimer’s and Parkinson’s. While genetic predispositions play a role in susceptibility, the cumulative effects of aging, combined with environmental and lifestyle factors, contribute to the increased likelihood of developing these conditions as you get older.

8. I sometimes forget things; could it be an early genetic sign?

Occasional forgetfulness is common, but if you have a strong family history, it’s natural to be concerned. While subtle cognitive changes can be symptoms of nervous system diseases, they are complex. Genetic testing can identify predispositions, but it’s crucial to consult a doctor for a full evaluation, as many factors can cause memory issues, and genetic risk is just one piece of the puzzle.

9. If I have a genetic risk, will it affect my ability to work or drive?

A genetic risk alone doesn’t mean your daily function will be immediately affected. However, if a nervous system disease develops, it can indeed impact movement, sensation, and cognition, which are crucial for daily activities like work or driving. Understanding your genetic predisposition can help you monitor for symptoms and engage in proactive health management with your doctor.

10. If a nervous system disease runs in my family, is there a genetic cure?

Unfortunately, most nervous system diseases currently lack a cure, even if there’s a strong genetic component. Advancements in treatment focus on managing symptoms, slowing disease progression, and improving functional abilities rather than a cure. Continued research into genetic factors, however, holds the promise for developing more targeted therapies and preventative strategies in the future.

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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] Beecham GW. et al. “Genome-wide association study implicates a chromosome 12 risk locus for late-onset Alzheimer disease.”Am J Hum Genet, vol. 84, no. 1, 2009, pp. 35-43.

[2] Harold, D., et al. “Genome-Wide Association Study Identifies Variants at CLU and PICALM Associated with Alzheimer’s Disease.”Nat Genet, 2009.

[3] Reiman EM. et al. “GAB2 alleles modify Alzheimer’s risk in APOE epsilon4 carriers.” Neuron, vol. 54, no. 5, 2007, pp. 713-21.

[4] Pankratz N. et al. “Genomewide association study for susceptibility genes contributing to familial Parkinson disease.”Hum Genet, vol. 124, no. 6, 2008, pp. 593-602.

[5] Wrensch M. et al. “Variants in the CDKN2B and RTEL1 regions are associated with high-grade glioma susceptibility.” Nat Genet, vol. 41, no. 8, 2009, pp. 820-25.

[6] Shete S. et al. “Genome-wide association study identifies five susceptibility loci for glioma.” Nat Genet, vol. 41, no. 8, 2009, pp. 899-904.

[7] Wellcome Trust Case Control Consortium. “Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.” Nature, 2007.

[8] Bertram, L., et al. “Genome-wide association analysis reveals putative Alzheimer’s disease susceptibility loci in addition to APOE.”Am J Hum Genet, vol. 83, no. 5, 2008, pp. 623-32.

[9] Abraham, R., et al. “A genome-wide association study for late-onset Alzheimer’s disease using DNA pooling.”BMC Med Genomics, vol. 1, no. 44, 2008.

[10] Lunetta, Kathryn L., et al. “Genetic correlates of longevity and selected age-related phenotypes: a genome-wide association study in the Framingham Study.” BMC Medical Genetics, vol. 8, suppl. 1, 2007, p. S13.

[11] Samani NJ. et al. “Genomewide association analysis of coronary artery disease.”N Engl J Med, vol. 357, no. 5, 2007, pp. 443-53.

[12] Duerr, RH. et al. “A genome-wide association study identifies IL23R as an inflammatory bowel disease gene.”Science, 2006.