Geographic Atrophy Lesion Growth
Introduction
Section titled “Introduction”Geographic atrophy (GA) lesion growth refers to the progressive expansion of areas of irreversible degeneration within the retina, specifically affecting the macula. It represents an advanced, non-neovascular form of Age-related Macular Degeneration (AMD), a leading cause of vision loss among older adults.[1] Unlike the “wet” form of AMD (choroidal neovascularization), GA is characterized by the gradual loss of photoreceptors, the retinal pigment epithelium (RPE), and the underlying choriocapillaris, which are crucial for maintaining healthy vision.
Biological Basis
Section titled “Biological Basis”The biological basis of geographic atrophy lesion growth involves complex processes of cellular dysfunction, oxidative stress, inflammation, and immune dysregulation within the macula. These lead to the death of retinal cells and the formation of distinct, sharply demarcated atrophic lesions. The rate at which these lesions enlarge is a key indicator of disease progression. Genetic factors are known to significantly influence both the susceptibility to AMD and the progression of the disease, including GA lesion growth.[1]Genome-wide association studies (GWAS) are employed to identify specific genetic variants, such as single nucleotide polymorphisms (SNPs), that are associated with quantitative traits like atrophy, providing insights into the molecular pathways involved in degeneration.[2]
Clinical Relevance
Section titled “Clinical Relevance”Monitoring geographic atrophy lesion growth is clinically critical for assessing disease severity, predicting future vision loss, and evaluating the effectiveness of potential treatments. As GA lesions expand, they progressively destroy central vision, impacting a patient’s ability to read, recognize faces, and perform other daily activities that require fine visual acuity. Early detection and precise measurement of lesion growth rates allow clinicians to better counsel patients, manage expectations, and potentially intervene with emerging therapies aimed at slowing the progression of atrophy.
Social Importance
Section titled “Social Importance”Geographic atrophy, as a major component of advanced AMD, carries significant social importance due to its profound impact on public health. It contributes substantially to the global burden of irreversible vision impairment and blindness in the elderly population. The loss of central vision associated with GA can severely diminish an individual’s quality of life, leading to reduced independence, increased risk of falls, social isolation, and a greater need for assistive care. Understanding the genetic and biological mechanisms driving GA lesion growth is crucial for developing preventative strategies and effective treatments, thereby alleviating the substantial personal and societal costs associated with this debilitating condition.
Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”Studies investigating the genetics of geographic atrophy lesion growth often face significant methodological and statistical challenges. Sample sizes in several studies were considerably smaller than those in larger consortia, which limited the statistical power to detect genetic variants with small effect sizes.[3]This underpowering means that many true associations, particularly for complex traits like geographic atrophy lesion growth that are likely influenced by numerous genes of small individual effect, may have been missed or presented only as suggestive findings.[3] Consequently, the observed significant results might represent an overestimation of effect sizes, and the lack of consistent replication across studies further underscores these power limitations and the potential for false positives.[3] Moreover, some analyses did not correct for multiple testing, meaning that nominally significant findings might not withstand more stringent statistical thresholds.[3] The heterogeneity in genotyping platforms and imputation strategies across different cohorts, where studies used varied GWAS arrays and imputed to different reference panels with varying quality thresholds, can introduce technical variability and contribute to discrepancies in findings during meta-analyses.[4] These technical differences complicate the combination and comparison of results, potentially obscuring true genetic signals or leading to spurious associations due to platform-specific biases.
Phenotypic Definition and Measurement Variability
Section titled “Phenotypic Definition and Measurement Variability”The assessment of geographic atrophy lesion growth often relies on imaging data acquired from diverse scanners and protocols across multiple study sites.[3] Such methodological heterogeneity in image acquisition, including differences in scanner types and calibration, can introduce measurement variability that complicates direct comparisons and meta-analyses, despite efforts to adjust for scanner effects.[3] The use of both semi-quantitative and more precise quantitative measures for lesion progression further adds to this challenge, making it difficult to combine data and accurately estimate effect sizes across studies.[5]Furthermore, the precise definition of geographic atrophy lesion growth itself can vary, with some studies using visual ratings and others employing volumetric changes, potentially impacting the consistency and comparability of phenotypic assessment.[4] Differences in covariates used for adjustment, such as age, sex, scanner, and intracranial volume, also contribute to result discrepancies and make it challenging to isolate the specific genetic influences on geographic atrophy progression.[3] These variations in phenotyping and measurement introduce noise, which can dilute genetic signals and hinder the identification of robust associations.
Generalizability and Population Ancestry
Section titled “Generalizability and Population Ancestry”Many studies investigating genetic influences on geographic atrophy lesion growth primarily involve cohorts of European ancestry, which limits the generalizability of findings to other populations.[4] Population stratification and diverse ancestries within combined cohorts necessitate careful adjustment, often through principal component analysis, to mitigate confounding by genetic background.[5] However, even with such adjustments, genetic effects might vary across different ancestral groups due to distinct allele frequencies or linkage disequilibrium patterns, making direct extrapolation challenging.[5] Significant demographic differences, including age and health status, exist between cohorts contributing to meta-analyses.[3]For instance, some cohorts may include individuals with mild cognitive impairment or Alzheimer’s disease alongside cognitively normal participants, potentially enriching the sample for specific atrophy patterns but introducing confounding factors for disease progression.[3] These cohort-specific characteristics can introduce bias and contribute to heterogeneity in results, requiring cautious interpretation of pooled findings and highlighting the need for more diverse and uniformly characterized study populations.
Unexplored Etiology and Knowledge Gaps
Section titled “Unexplored Etiology and Knowledge Gaps”Geographic atrophy lesion growth, as a complex trait, is likely influenced by numerous genetic variants, each contributing a small individual effect.[3] Current research, while identifying suggestive loci, indicates that a substantial portion of the heritability remains unexplained, a phenomenon often referred to as ‘missing heritability’.[3] This suggests that the interplay of common variants with small effects, rare variants, and gene-environment interactions may contribute significantly to the trait, which current study designs may not fully capture.
Furthermore, the genetic influences on the progression of age-related macular degeneration subtypes, including geographic atrophy, are largely unexplored compared to studies on disease susceptibility.[6] Future research should prioritize longitudinal studies over extended periods to better capture the dynamic nature of lesion growth and identify genetic variants that influence its trajectory across the lifespan.[3] Addressing these gaps requires larger, more diverse cohorts with harmonized longitudinal imaging data and advanced statistical methods capable of unraveling complex genetic architectures and environmental interactions.
Variants
Section titled “Variants”Genetic variations play a crucial role in influencing various biological processes, including those related to neurodegeneration and ocular health, such as geographic atrophy lesion growth. The variantrs2839127 is located within the _FTCD_gene, which encodes formiminotransferase cyclodeaminase, an enzyme essential for histidine and folate metabolism._FTCD_is involved in converting formiminoglutamate (FIGLU) to glutamate, a reaction that requires tetrahydrofolate as a co-factor. Alterations in_FTCD_ activity due to variants like rs2839127 can impact folate levels and cellular metabolic pathways, which are critical for DNA synthesis, repair, and overall cellular function.[5] Such metabolic disruptions can contribute to cellular stress and inflammation, factors implicated in the progression of age-related conditions, including white matter hyperintensities and geographic atrophy.[4] Another significant locus involves rs11184959 , situated in a region encompassing _LINC01677_ and _MTATP6P14_. _LINC01677_ is a long intergenic non-coding RNA, which typically functions in regulating gene expression, influencing processes like cell growth, differentiation, and stress responses. _MTATP6P14_ is a pseudogene related to _MT-ATP6_, a critical mitochondrial gene responsible for producing a subunit of ATP synthase, vital for cellular energy production. Variants in this region, such asrs11184959 , could affect the regulatory activity of _LINC01677_ or influence the expression and function of the active _MT-ATP6_ gene through its pseudogene counterpart.[2]Disruptions in mitochondrial function and energy metabolism are hallmarks of many age-related neurodegenerative diseases, including hippocampal atrophy and the retinal pigment epithelium cell death characteristic of geographic atrophy.[2] The variant rs145146260 is found within the _DISC1FP1_ gene, which is a fusion partner of _DISC1_(Disrupted in Schizophrenia 1). While_DISC1FP1_ itself is not as extensively studied as _DISC1_, its association suggests a potential role in neural development and function, possibly by modulating _DISC1_-related pathways. _DISC1_ is known to be involved in neuronal migration, proliferation, and synaptic plasticity, processes fundamental to brain health.[7] Variants like rs145146260 could influence the expression or stability of _DISC1FP1_, thereby indirectly affecting cellular resilience, programmed cell death (apoptosis), or cell-cell interactions within neural tissues, including the retina.[8] Such impacts on cellular integrity and function could contribute to the vulnerability of retinal cells to damage and the progression of geographic atrophy.
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs2839127 | FTCD | geographic atrophy lesion growth |
| rs11184959 | LINC01677 - MTATP6P14 | geographic atrophy lesion growth |
| rs145146260 | DISC1FP1 | geographic atrophy lesion growth |
Definition and Clinical Classification of Geographic Atrophy
Section titled “Definition and Clinical Classification of Geographic Atrophy”Geographic Atrophy (GA) represents one of the advanced forms of age-related macular degeneration (AMD), which is a leading cause of irreversible vision loss in older adults. It is precisely characterized by the atrophy of macular neurosensory cells, a critical feature distinguishing it at a tissue level. This specific cellular degeneration forms the core of its pathological definition within the spectrum of AMD.[1]As a primary subtype of advanced AMD, GA is classified distinctly from choroidal neovascularization (CNV), the other major advanced form. These two subtypes are understood to segregate separately in families and possess distinct pathological pathways. The classification into GA versus CNV is crucial for understanding disease mechanisms and potential therapeutic approaches, given their differing clinical presentations.[1]
Nature and Terminology of Progression
Section titled “Nature and Terminology of Progression”The progression of geographic atrophy is generally described as a slowly progressive process. This gradual advancement of macular neurosensory cell atrophy defines the temporal aspect of the disease. This slow progression stands in contrast to choroidal neovascularization, which frequently manifests with an acute onset.[1]
Causes of Geographic Atrophy Lesion Growth
Section titled “Causes of Geographic Atrophy Lesion Growth”Geographic atrophy (GA) lesion growth, a progressive form of vision loss, is primarily driven by a complex interplay of genetic factors and the aging process. While research has identified key contributors to the susceptibility of developing geographic atrophy, the specific mechanisms and factors directly influencing the rate and extent of lesion expansion are areas of ongoing investigation.
Genetic Predisposition to Geographic Atrophy
Section titled “Genetic Predisposition to Geographic Atrophy”The development and progression of geographic atrophy lesions are significantly influenced by an individual’s genetic makeup. Studies on advanced age-related macular degeneration (AMD) subtypes, including GA, reveal that the condition segregates within families, strongly indicating an inherited component.[1]Genome-wide association studies (GWAS) have successfully identified multiple disease-susceptibility loci for AMD, suggesting a polygenic risk where various genetic variants collectively contribute to the likelihood of developing geographic atrophy.[6]While these genetic associations are well-established for disease susceptibility, the specific genetic influences governing the actual rate of lesion progression or growth are noted to be largely unexplored.[6]
Age as a Primary Contributor
Section titled “Age as a Primary Contributor”The fundamental role of age in the development and expansion of geographic atrophy lesions is inherent in its classification as a subtype of Age-related Macular Degeneration (AMD).[1]As an age-dependent condition, the physiological changes associated with advancing age are critical drivers of GA lesion formation and subsequent growth. These long-term, age-related processes likely contribute to cumulative cellular dysfunction and the accumulation of waste products in the macula, thereby creating an environment conducive to the progressive atrophy of retinal pigment epithelial cells and photoreceptors. Therefore, advanced age is not merely a risk factor but a foundational element in the pathogenesis leading to geographic atrophy lesion growth.
Pathophysiology of Geographic Atrophy
Section titled “Pathophysiology of Geographic Atrophy”Geographic atrophy (GA) represents an advanced form of age-related macular degeneration (AMD), characterized by a slowly progressive degeneration of the macular neurosensory cells.[1] This process culminates in the formation of distinct atrophic lesions within the macula, the central part of the retina responsible for sharp, detailed vision. The clinical and histological features of GA suggest unique pathological pathways compared to other advanced AMD subtypes, such as choroidal neovascularization (CNV).[1] The “lesion growth” aspect of GA signifies the ongoing loss of critical retinal cells, including photoreceptors, retinal pigment epithelium (RPE), and choriocapillaris, leading to irreversible vision loss.
The progression of GA involves a breakdown in the homeostatic balance of the retinal environment. As macular neurosensory cells atrophy, their essential functions, such as light detection and processing, are compromised. This cellular demise reflects a failure in the complex interactions between various retinal tissue layers, ultimately leading to the characteristic geographic areas of cell death and tissue thinning observed clinically.[1] Understanding the mechanisms driving this progressive atrophy is crucial for addressing the continuous expansion of these lesions.
Genetic Underpinnings of Age-Related Macular Degeneration
Section titled “Genetic Underpinnings of Age-Related Macular Degeneration”Genetic factors play a significant role in the susceptibility to age-related macular degeneration, including its advanced forms like geographic atrophy. Family- and population-based genetic studies, particularly genome-wide association studies (GWAS), have successfully identified multiple disease-susceptibility loci for AMD.[6]These genetic variants, such as single nucleotide polymorphisms (SNPs), can influence an individual’s risk of developing AMD and may also contribute to the distinct pathological pathways observed in GA versus CNV.[1] The identification of specific genetic differences between advanced AMD subtypes is an ongoing area of research.[1]While significant progress has been made in identifying genetic loci associated with AMD susceptibility, the genetic influences on the progression of the disease, including the rate of geographic atrophy lesion growth, are largely unexplored.[6]Genetic mechanisms can impact disease progression through various means, including alterations in gene expression patterns, the function of critical proteins, or regulatory elements within the genome.[2]The analysis of imaging phenotypes, such as atrophy, as quantitative traits in GWAS, provides a powerful approach to uncover these genetic influences on disease progression.[2]
Molecular and Cellular Pathways in Retinal Atrophy
Section titled “Molecular and Cellular Pathways in Retinal Atrophy”The cellular and tissue atrophy characteristic of geographic atrophy involves disruptions in fundamental molecular and cellular pathways. Normal cellular functions, including metabolic processes, cellular maintenance, and survival, are meticulously regulated by complex signaling pathways and regulatory networks. The degeneration of macular neurosensory cells in GA suggests a failure in these critical processes, leading to cellular dysfunction and eventual cell death.[1] Key biomolecules, such as enzymes, receptors, and transcription factors, are integral to these pathways, orchestrating cellular responses and maintaining tissue integrity.
Genetic variants identified through studies like GWAS can influence the expression of genes and the function of their encoded proteins, thereby impacting these intricate cellular mechanisms.[2] For instance, variations in the DNA sequence, including those within exons that are transcribed into RNA and translated into proteins, can alter protein structure or abundance.[2] Additionally, regulatory elements can modulate gene expression patterns, influencing cellular health and susceptibility to atrophy. While specific molecular pathways directly linked to GA lesion growth are still being elucidated, the general principles of cellular regulation, metabolism, and response to stress are central to understanding the progression of atrophy in the macula.
Cellular Communication and Signal Transduction
Section titled “Cellular Communication and Signal Transduction”Cellular communication is orchestrated by intricate signaling pathways that regulate diverse cellular functions, including growth, differentiation, and survival. Receptor activation, such as that involving G-protein coupled receptors or tyrosine kinase receptors like EGFR, initiates intracellular signaling cascades.[7] These cascades often involve secondary messengers, like calcium, and can include components such as PIP5K3 and MCTP2 in calcium-mediated signaling.[7] The endothelin receptor system, which includes receptors for EDN1, EDN2, and EDN3, also plays a role in mediating cellular responses, particularly in glial cells, influencing processes like mitogenesis.[9] Such intricate networks are crucial for maintaining cellular homeostasis and coordinating tissue-level responses. Additionally, pathways like WNT signaling contribute to embryogenesis and cell-cell interactions, highlighting their fundamental role in tissue organization and development.[8]
Metabolic Regulation and Energy Homeostasis
Section titled “Metabolic Regulation and Energy Homeostasis”Metabolic pathways are fundamental for energy production, biosynthesis, and catabolism, ensuring the cell’s functional integrity. Amino acid metabolism, involving transporters likeSLC6A6 and SLC7A5, is essential for protein synthesis and cellular energy balance.[7] Lipid metabolism, including the elongation of long-chain fatty acids mediated by enzymes like ELOVL7, is critical for maintaining membrane structure and signaling.[10]Furthermore, processes like purine degradation contribute to nucleotide recycling, and components such asNDUFAF2 are linked to mitochondrial energy metabolism, underscoring the importance of tightly controlled metabolic flux for overall cellular health.[8], [11]
Genetic and Post-Translational Control
Section titled “Genetic and Post-Translational Control”Regulatory mechanisms at both the genetic and protein levels dictate cellular responses and adaptations. Transcription factors, which can be influenced by upstream signaling cascades, regulate gene expression by binding to specific DNA sequences, thereby controlling the synthesis of proteins necessary for cellular function.[8] Beyond gene regulation, proteins undergo various post-translational modifications and are subject to quality control mechanisms like the proteasome system.[12] Dysregulation in protein degradation, such as proteasome impairment, can lead to the accumulation of misfolded or aggregated proteins, impacting cellular viability and tissue health.[12]
Tissue Integrity and Cellular Dynamics
Section titled “Tissue Integrity and Cellular Dynamics”Maintaining tissue integrity involves a delicate balance of cell-cell interactions, adhesion, and controlled cell movement. Calcium-dependent cell adhesion mechanisms are vital for establishing and maintaining tissue architecture, ensuring cells remain properly connected within their environment.[8] The biogenesis of connective tissue components, including microfibrils, provides structural support and elasticity to tissues, which is essential for their mechanical stability.[8] Moreover, the regulation of cell migration, influenced by factors like JAG1 and EGFR, is crucial for tissue repair and remodeling processes, allowing cells to move precisely in response to physiological demands.[7]
Prognostic Insights into Geographic Atrophy Progression
Section titled “Prognostic Insights into Geographic Atrophy Progression”Geographic atrophy (GA) represents a slowly progressive form of advanced age-related macular degeneration (AMD), characterized by the gradual atrophy of macular neurosensory cells.[1] This inherent slow progression provides critical prognostic information, distinguishing it from the often acute vision loss associated with choroidal neovascularization (CNV).[1]Understanding this progressive nature is vital for predicting long-term visual outcomes and for patient education regarding the trajectory of their disease. The rate of this progression, while generally slow, dictates the timeline for significant vision impairment, influencing patient counseling and long-term care planning.
Diagnostic Utility and Monitoring Strategies
Section titled “Diagnostic Utility and Monitoring Strategies”The distinct clinical characteristics and histological features of geographic atrophy (GA) compared to choroidal neovascularization (CNV) offer significant diagnostic utility for clinicians.[1]Accurate differentiation between these two advanced AMD subtypes is crucial for tailoring patient management and monitoring strategies. For GA, monitoring focuses on tracking the expansion of atrophic lesions over time, which helps in assessing disease activity and the potential for future vision loss. This targeted diagnostic approach is essential for guiding clinical decision-decision-making and for the development of specific therapeutic interventions that address the unique pathology of GA.
Genetic Risk Stratification and Future Therapies
Section titled “Genetic Risk Stratification and Future Therapies”Genome-wide association studies (GWAS) and sibling correlation studies are instrumental in identifying genetic variants that influence geographic atrophy (GA) and differentiate it from choroidal neovascularization (CNV).[1] These studies aim to understand whether GA segregates uniquely within families and to pinpoint specific genetic underpinnings.[1] Such genetic insights are vital for robust risk stratification, enabling the identification of high-risk individuals before significant lesion growth occurs. By elucidating the genetic landscape of GA, these studies lay the groundwork for personalized medicine approaches, potentially leading to the development of targeted prevention strategies and therapies. The recognition of distinct pathological pathways for GA, supported by genetic evidence, suggests that treatments specifically designed to halt or slow lesion growth could be more effective than broad AMD interventions.[1] Further research into these genetic differences is crucial for advancing therapeutic options and improving patient care.
Frequently Asked Questions About Geographic Atrophy Lesion Growth
Section titled “Frequently Asked Questions About Geographic Atrophy Lesion Growth”These questions address the most important and specific aspects of geographic atrophy lesion growth based on current genetic research.
1. My parent’s GA got bad quickly; will mine too?
Section titled “1. My parent’s GA got bad quickly; will mine too?”Yes, there’s often a strong genetic component to how quickly geographic atrophy progresses. If your parent experienced rapid lesion growth, you may have inherited similar genetic factors that influence the speed of tissue degeneration. However, individual disease courses can still vary, as many factors contribute to progression.
2. Why does my GA seem to grow faster than my friend’s?
Section titled “2. Why does my GA seem to grow faster than my friend’s?”The rate of geographic atrophy growth is significantly influenced by your unique genetic makeup. Specific genetic variations can impact the underlying biological processes, such as inflammation or cellular repair, making your lesions expand faster than someone else’s, even if other factors are similar.
3. Can my daily habits actually slow down my GA?
Section titled “3. Can my daily habits actually slow down my GA?”While genetic factors play a significant role in GA progression, lifestyle and daily habits can still influence the disease course. Although specific habits aren’t detailed, maintaining overall good health and following medical advice are generally recommended to support eye health and potentially help slow down degeneration, even with a genetic predisposition.
4. Can a genetic test tell me how fast my GA will grow?
Section titled “4. Can a genetic test tell me how fast my GA will grow?”Genetic tests can identify specific variants associated with geographic atrophy susceptibility and its progression. While they can indicate your general risk and likelihood of faster growth, predicting an exact, precise rate is complex because many genes and other individual factors are involved. It provides valuable insights, but not a definitive timeline.
5. Does my family’s non-European background change my GA risk?
Section titled “5. Does my family’s non-European background change my GA risk?”Yes, research suggests that genetic risk factors for geographic atrophy can vary across different ancestral groups. Most studies have focused on people of European descent, so the specific genetic influences and their impact on lesion growth might be different for individuals with other ethnic backgrounds.
6. If my GA is genetic, can anything truly stop it?
Section titled “6. If my GA is genetic, can anything truly stop it?”Geographic atrophy involves irreversible cell loss, and currently, there’s no cure to completely stop its progression, especially if you have strong genetic predispositions. However, emerging therapies are being developed to slow down the growth, and managing overall health can support eye health and preserve vision longer.
7. Will my children definitely get GA if I have it?
Section titled “7. Will my children definitely get GA if I have it?”Having geographic atrophy increases your children’s risk, as genetic factors are strongly involved in both susceptibility and progression. However, it’s not a certainty that they will develop it, or that it will progress at the same rate. They inherit a predisposition, but other genetic and environmental factors also play a role.
8. Why do some people’s GA barely grow, but others lose vision fast?
Section titled “8. Why do some people’s GA barely grow, but others lose vision fast?”This significant difference in progression speed is largely due to individual genetic variations. Some people inherit genetic profiles that lead to a slower, less aggressive form of GA. In contrast, others have genetic markers that contribute to faster, more severe degeneration and quicker vision loss.
9. Can knowing my genetics help me prepare for future vision loss?
Section titled “9. Can knowing my genetics help me prepare for future vision loss?”Yes, understanding your genetic predisposition for geographic atrophy progression can be very helpful. It allows you and your doctor to monitor your eyes more closely, anticipate potential vision changes, and discuss early interventions or adaptive strategies to maintain your quality of life as effectively as possible.
10. Why do I hear different things about what causes GA growth?
Section titled “10. Why do I hear different things about what causes GA growth?”Research into geographic atrophy is complex, and studies often face challenges like small sample sizes, or differences in how they define and measure lesion growth. This can lead to findings that don’t always perfectly align or are hard to replicate, which might explain why you hear varied information about its causes and progression.
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
Section titled “References”[1] Sobrin L, et al. “Heritability and genome-wide association study to assess genetic differences between advanced age-related macular degeneration subtypes.”Ophthalmology, 2012.
[2] Potkin SG, et al. “Hippocampal atrophy as a quantitative trait in a genome-wide association study identifying novel susceptibility genes for Alzheimer’s disease.”PLoS One, 2009.
[3] Mather, K. A., et al. “Investigating the genetics of hippocampal volume in older adults without dementia.”PLoS One, vol. 10, no. 1, 2015, e0116240.
[4] Hofer, E., et al. “White Matter Lesion Progression: Genome-Wide Search for Genetic Influences.” Stroke, vol. 47, no. 2, 2016, pp. 332-9.
[5] Melville, S. A., et al. “Multiple loci influencing hippocampal degeneration identified by genome scan.” Annals of Neurology, vol. 72, no. 1, 2012, pp. 42-52.
[6] Yan, Q. et al. “Genome-wide Analysis of Disease Progression in Age-related Macular Degeneration.”Hum Mol Genet, vol. 27, no. 4, 2018, pp. 744–53.
[7] Baranzini SE. “Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis.”Hum Mol Genet, 2009.
[8] Sailer A, et al. “A genome-wide association study in multiple system atrophy.” Neurology, 2016.
[9] MacCumber MW, Ross CA, Snyder SH. “Endothelin in brain: receptors, mitogenesis, and biosynthesis in glial cells.” Proc Natl Acad Sci USA, 1990.
[10] Leonard AE, Pereira SL, Sprecher H, Huang YS. “Elongation of long-chain fatty acids.” Prog Lipid Res, 2004.
[11] Janssen RJ, Distelmaier F, Smeets R, et al. “Contiguous gene deletion of ELOVL7, ERCC8 and NDUFAF2 in a patient with a fatal multisystem disorder.” Hum Mol Genet, 2009.
[12] Deger JM, Gerson JE, Kayed R. “The interrelationship of proteasome impairment and oligomeric intermediates in neurodegeneration.” Aging Cell, 2015.