Infectious Disease

Infectious diseases are illnesses caused by pathogenic microorganisms, such as bacteria, viruses, fungi, or parasites, that invade the body and multiply. These diseases can range from mild, self-limiting conditions to severe, life-threatening illnesses, and they represent a significant challenge to global health. Historically, infectious diseases have shaped human populations, causing epidemics and pandemics that have led to widespread mortality and societal disruption.

The biological basis of an infectious disease involves a complex interaction between the invading pathogen and the host’s immune system. Upon exposure, the pathogen attempts to establish infection, while the host’s immune defenses work to detect, neutralize, and eliminate the invader. The outcome of this interaction—whether an individual becomes infected, develops symptoms, or experiences severe disease—is influenced by various factors, including the pathogen’s virulence and the host’s genetic makeup. Genetic variations in individuals can affect the strength and specificity of their immune response, influencing susceptibility or resistance to particular pathogens, as well as the severity and progression of an infection. Studies have identified genetic loci associated with susceptibility to various complex conditions, including immune-mediated diseases such as Crohn’s disease^[1], ^[2], ^[3]and celiac disease^[4], as well as inflammatory conditions like Kawasaki disease^[5]. This highlights the broader principle that an individual’s genetic profile plays a role in their response to disease challenges.

Clinically, infectious diseases are a primary focus of medical practice. Diagnosis involves identifying the specific pathogen, often through laboratory tests, to guide appropriate treatment. Treatment strategies typically include antimicrobial medications like antibiotics for bacterial infections, antivirals for viral infections, antifungals, or antiparasitics. Prevention is paramount, relying on public health measures such as vaccination programs, sanitation, hygiene practices, and infection control within healthcare settings. Understanding the genetic predispositions to infectious diseases can pave the way for more personalized preventive strategies and therapeutic interventions.

The social importance of infectious diseases is immense, impacting public health, economic stability, and global security. Outbreaks can overwhelm healthcare systems, disrupt travel and trade, and lead to significant economic losses. Public health initiatives, international collaborations, and ongoing research are crucial for monitoring emerging pathogens, developing new vaccines and treatments, and implementing effective strategies to control the spread of infections and mitigate their societal impact.

Limitations

Genome-wide association studies (GWAS) of infectious diseases, while powerful, are subject to several inherent limitations that influence the interpretation and generalizability of their findings. These constraints typically arise from study design, population characteristics, and the complex interplay of genetic and environmental factors.

Methodological and Statistical Constraints

The ability of GWAS to detect all relevant genetic associations is often limited by statistical power and study design. Many studies, particularly for rarer conditions, operate with modest sample sizes, which can result in insufficient power to detect genetic variants with small to moderate effect sizes, such as an odds ratio of 2.0 ^[5]. This limitation means that a substantial portion of true genetic susceptibility loci may remain undiscovered, leading to an incomplete understanding of disease etiology. Furthermore, the inherent need for stringent statistical thresholds in genome-wide analyses to account for multiple comparisons can further mask associations of moderate effect, necessitating replication studies to confirm initial findings and reduce the risk of spurious associations^[6]. Incomplete genomic coverage by genotyping platforms, especially concerning rare variants or structural variations, also means that not all common or rare genetic variations contributing to disease susceptibility are assessed, thus limiting the comprehensiveness of the genetic landscape uncovered^[6].

Phenotypic Definition and Population Generalizability

The precision of phenotype definition is a critical factor influencing GWAS results. For diseases where the phenotype is clinically defined, as in some infectious diseases, variability in diagnostic criteria or disease presentation can introduce heterogeneity into study cohorts. Such inconsistencies can obscure genuine genetic signals or lead to a weaker association than truly exists, complicating the identification of robust genetic risk factors^[5]. Additionally, findings from GWAS are often specific to the ancestral populations studied, raising concerns about their generalizability. Population stratification, where genetic differences between subgroups within a study cohort can lead to spurious associations, must be carefully addressed through methods like EIGENSTRAT correction ^[7]. Consequently, genetic associations identified in one population may not translate directly to other diverse populations, highlighting the need for broader representation in research to ensure global applicability of findings.

Incomplete Genetic Architecture and Environmental Influences

Despite the success of GWAS in identifying numerous genetic loci, a significant portion of the heritability for many diseases, including susceptibility to infectious agents, remains unexplained—a phenomenon known as “missing heritability.” This indicates that the identified common variants account for only a fraction of the total genetic contribution to disease risk^[6]. The remaining heritability is likely attributable to a complex interplay of factors, including rarer genetic variants, gene-gene interactions, and crucially, gene-environment interactions. Environmental exposures, lifestyle factors, and other non-genetic elements are known to profoundly influence disease susceptibility and progression, yet these are often not comprehensively captured or integrated into GWAS analyses. Without a detailed understanding of these environmental confounders and their interactions with genetic predispositions, the full picture of disease etiology remains elusive, limiting the predictive and mechanistic insights derived solely from genetic data.

Variants

The human genetic landscape features numerous variations that profoundly influence individual susceptibility to a wide spectrum of health conditions, including how the body responds to infectious agents. Among these are variants associated with genes like LINC02866 and TCF7L2, each playing distinct yet critical roles in cellular regulation and metabolic processes. LINC02866, a long intergenic non-coding RNA (lncRNA), represented by the variant rs187844901 , does not encode a protein but instead acts as a regulatory molecule, modulating the expression of nearby or distant protein-coding genes. LncRNAs are increasingly recognized for their involvement in fine-tuning immune responses and inflammatory pathways, which are essential for defending against infections. Alterations in their activity, potentially induced by variants like rs187844901 , could therefore modify the body’s defense mechanisms. Similarly, the TCF7L2 gene encodes a transcription factor central to the Wnt signaling pathway, a fundamental cellular communication system vital for development and tissue maintenance. The variant rs7903146 in TCF7L2 is a well-established genetic marker strongly associated with an increased risk of type 2 diabetes, a metabolic condition known to compromise immune function and heighten vulnerability to numerous infections ^[6]

Another crucial gene in this context is GPC1, or Glypican 1, which encodes a cell surface heparan sulfate proteoglycan. The variant rs191571179 within GPC1 could potentially influence the structure or expression level of this protein, thereby affecting its diverse roles in cellular communication. Glypicans function as co-receptors, modulating the activity of growth factors and other signaling molecules essential for cell growth, differentiation, and tissue repair. Importantly, heparan sulfate proteoglycans, including GPC1, are frequently utilized by various pathogens, such as viruses and bacteria, as attachment sites or co-receptors to facilitate their entry into host cells. Consequently, variations in GPC1, like rs191571179 , could impact the initial stages of infection, potentially altering an individual’s susceptibility or resistance to specific infectious agents. Understanding these genetic influences on host-pathogen interactions is vital for elucidating the complex interplay between human genetics and disease outcomes, as demonstrated by studies exploring susceptibility loci for various conditions^[8]

Key Variants

RS ID	Gene	Related Traits
rs187844901	LINC02866	infectious disease
rs7903146	TCF7L2	insulin measurement clinical laboratory measurement, glucose measurement body mass index type 2 diabetes mellitus type 2 diabetes mellitus, metabolic syndrome
rs191571179	U3 - GPC1	infectious disease

Conceptualizing Infectious Diseases: Etiology and Susceptibility

An infectious disease is fundamentally characterized by the body’s response to one or more infectious triggers. This conceptual framework often involves the interaction between environmental agents and the host’s genetic makeup, where genetically susceptible individuals may develop the condition^[5]. The absence of a consistently identified etiologic agent for certain conditions, such as Kawasaki disease, underscores the complexity in precisely defining and understanding the pathogenesis of some infectious diseases^[5]. This lack of a clear agent can significantly impede the development of accurate diagnostic tools and effective management strategies ^[5].

Diagnostic Criteria and Measurement Approaches

Accurate and timely diagnosis of infectious diseases relies heavily on established diagnostic criteria, which often involve clinical presentation and observable traits. In research contexts, conditions like diabetes, hypertension, and hyperlipidemia are identified as risk factors based on meeting specific diagnostic criteria or receiving treatment for these conditions^[9]. For infectious diseases, the challenge of identifying a consistent etiologic agent, as noted in Kawasaki disease, directly impacts the precision of measurement approaches and the ability to define clear diagnostic thresholds^[5]. This difficulty in pinpointing a specific infectious trigger can hamper the development of optimal management strategies, necessitating reliance on clinical criteria for operational definitions of the disease^[5].

Classification Systems and Nomenclature

The classification of infectious diseases, even those with an elusive primary cause, typically involves nosological systems that categorize conditions based on their observable phenotypes and clinical characteristics. For instance, Kawasaki disease is recognized as a distinct entity despite the absence of a consistent etiologic agent, indicating that classification can proceed based on its clinical presentation and the body’s response to infectious triggers^[5]. Key terminology includes “infectious triggers” and “genetic susceptibility,” which are fundamental to understanding the pathogenesis of such conditions ^[5]. While the provided research does not detail specific severity gradations or subtypes for infectious diseases, the broader context of genome-wide association studies across various traits implies the use of categorical and potentially dimensional approaches to classify disease phenotypes for research purposes^[10].

Causes

The development of infectious disease is a complex process influenced by a range of host factors, particularly genetic predispositions that modulate immune responses and interactions with external triggers. Research into the genetic architecture of various conditions has illuminated how an individual’s inherited traits can significantly impact their susceptibility.

Genetic Predisposition and Immune Response

An individual’s genetic makeup plays a crucial role in determining their susceptibility to diseases with an immune component, including those potentially initiated by infectious agents. Specific inherited genetic variants can increase vulnerability by affecting the host’s immune system. For example, genetic risk variants for celiac disease have been identified that are directly related to the immune response, highlighting how specific genes influence immunological pathways^[4]. Similarly, studies on inflammatory bowel diseases, such as Crohn’s disease, have uncovered numerous susceptibility loci, some of which implicate critical immune processes like autophagy in disease pathogenesis^[1]. The identification of genes such as IL23R as an inflammatory bowel disease gene further underscores the importance of immune pathway regulation in the development of these conditions^[11].

These genetic factors often contribute to a polygenic risk, where multiple genes, rather than a single variant, collectively increase an individual’s vulnerability. Genome-wide association studies have revealed novel and functionally related susceptibility loci for conditions like Kawasaki disease, suggesting a complex genetic architecture underlies this inflammatory condition^[5]. Such genetic predispositions can alter the host’s ability to mount an effective immune response or lead to its dysregulation, thereby influencing the outcome when encountering specific environmental triggers.

Complex Genetic Architectures

The genetic basis of many complex diseases, including those with immune or inflammatory components, involves an intricate architecture characterized by numerous susceptibility loci distributed across the genome. For Crohn’s disease, genome-wide association studies have identified over 30 distinct susceptibility loci, illustrating the highly polygenic nature of the condition^[2], ^[1]. These large-scale studies analyze thousands of cases and controls to uncover common genetic variants that each contribute incrementally to overall disease risk^[6].

Beyond Crohn’s, other forms of inflammatory bowel disease, such as pediatric-onset inflammatory bowel disease, have shown associations with specific loci on chromosomes 20q13 and 21q22^[3]. The discovery of novel disease genes like NELL1 for inflammatory bowel disease further demonstrates the extensive array of genetic factors contributing to these conditions^[12]. These findings suggest that disease risk is often a result of the interplay between multiple genes, potentially involving gene-gene interactions that modulate the overall genetic susceptibility.

Interplay of Genetic Susceptibility with External Triggers

While genetic predisposition significantly influences an individual’s vulnerability to certain conditions, the manifestation of these diseases frequently involves an interaction with external environmental triggers. For conditions like Kawasaki disease, which has identified genetic susceptibility loci, it is hypothesized that an environmental factor, potentially an infection, acts upon a genetically predisposed individual to initiate the disease^[5]. Similarly, celiac disease, an autoimmune condition with strong genetic links, is known to be triggered by dietary gluten^[4].

This concept of gene-environment interaction highlights that inherited genetic variants do not operate in isolation but rather modulate the host’s response to various external exposures. The precise mechanisms by which environmental factors, including potential infectious agents, interact with an individual’s unique genetic profile to initiate or exacerbate complex diseases remain a key area of scientific investigation, particularly for conditions with a strong immune component.

Biological Background

Genetic Predisposition and Disease Risk

The susceptibility to various diseases is significantly influenced by an individual’s genetic makeup. Genome-wide association studies (GWAS) have been instrumental in identifying numerous genetic risk variants and susceptibility loci across the human genome for a range of common conditions, including autoimmune disorders such as celiac disease, Crohn’s disease, and inflammatory bowel disease (IBD), as well as cardiovascular conditions and neurodegenerative diseases^[4]. These studies pinpoint specific genetic markers that are more frequently observed in individuals affected by a disease, suggesting a role for these genomic regions in disease development.

These identified genetic variants often reside within or near genes that play critical roles in biological processes, impacting gene functions and expression patterns. For instance, specific alleles can modify disease risk, such as GAB2 alleles influencing Alzheimer’s disease risk in APOE epsilon4 carriers, or specific loci on chromosomes 20q13 and 21q22 being associated with pediatric-onset inflammatory bowel disease^[13]. The presence of such genetic variations can alter the production, structure, or function of critical proteins, enzymes, or receptors, thereby influencing an individual’s physiological responses and overall disease susceptibility.

Immune System Regulation and Cellular Pathways

The body’s immune system plays a central role in responding to various challenges, and its regulation involves intricate molecular and cellular pathways. Genetic variations can significantly impact these regulatory networks, leading to altered immune responses that contribute to disease pathogenesis. For example, the IL23R gene has been identified as an inflammatory bowel disease gene, highlighting the importance of specific receptors in mediating immune and inflammatory signaling pathways^[11]. Such receptors are key biomolecules that initiate cascades of cellular events, influencing immune cell activation, differentiation, and cytokine production.

Beyond specific receptors, fundamental cellular functions like autophagy are also implicated in disease pathogenesis, as seen in Crohn’s disease^[1]. Autophagy, a tightly regulated catabolic process, is crucial for maintaining cellular homeostasis by clearing damaged organelles and proteins, and its dysfunction can disrupt cellular processes and contribute to inflammatory conditions. These molecular and cellular pathways are interconnected, forming complex regulatory networks that, when perturbed by genetic factors or environmental cues, can lead to homeostatic disruptions and the development of immune-mediated diseases or altered susceptibility to various health challenges.

Pathophysiological Processes and Systemic Consequences

Diseases manifest through a series of pathophysiological processes that disrupt normal physiological function, extending from the cellular to the systemic level. Genetic predispositions, combined with environmental factors, can initiate disease mechanisms that lead to tissue damage and organ-specific effects. For instance, in conditions like celiac disease and inflammatory bowel disease, dysregulated immune responses can lead to chronic inflammation and damage within the gastrointestinal tract, affecting nutrient absorption and overall digestive health^[4]. Similarly, in cardiovascular diseases, genetic factors contribute to processes like subclinical atherosclerosis and coronary artery disease, impacting arterial territories and leading to systemic consequences^[9].

These localized disruptions can trigger compensatory responses, but prolonged or severe alterations can lead to widespread systemic consequences. Key biomolecules, including various proteins, enzymes, and structural components, are often central to these disease mechanisms, with their altered function or expression contributing to the pathology. Understanding these complex interactions at the tissue and organ level, and how genetic variants influence these processes, is crucial for elucidating the full spectrum of disease pathophysiology and developing targeted interventions.

Pathways and Mechanisms

The intricate interplay of host pathways governs susceptibility and response to infectious agents and immune challenges. Genetic variations can significantly modulate these pathways, influencing the body’s ability to maintain homeostasis, mount effective immune responses, or develop chronic inflammatory conditions. Insights from genome-wide association studies (GWAS) on immune-mediated diseases illuminate fundamental host mechanisms that are critical in disease pathogenesis, including those potentially triggered or exacerbated by infectious processes.

Immune Signaling and Inflammatory Regulation

Host defense against pathogens relies heavily on precise immune signaling pathways, which detect threats and orchestrate appropriate responses. Receptor activation initiates intracellular signaling cascades that propagate information from the cell surface to the nucleus, culminating in the regulation of transcription factors. For instance, genetic risk variants for celiac disease are linked to the immune response, highlighting how specific molecular cues activate pathways leading to immune-mediated damage^[4]. Similarly, the identification of IL23R as a susceptibility gene for inflammatory bowel disease underscores the critical role of cytokine receptor signaling in modulating inflammatory cascades and shaping immune cell behavior^[11]. Dysregulation within these finely tuned signaling networks can lead to either insufficient defense against pathogens or excessive inflammatory responses, contributing to disease.

Cellular Homeostasis and Autoregulatory Mechanisms

Maintaining cellular integrity and function is paramount for host survival, involving complex autoregulatory mechanisms like gene regulation, protein modification, and post-translational control. These processes ensure proper protein function and cellular turnover, which are crucial during periods of stress or infection. A key example is autophagy, a cellular degradation and recycling process implicated in the pathogenesis of Crohn’s disease^[1]. Genetic variants affecting the regulation of autophagy can alter a cell’s capacity to clear intracellular pathogens, remove damaged organelles, or present antigens, thereby influencing both immune function and overall cellular resilience. Such alterations in fundamental regulatory mechanisms can compromise the host’s ability to adapt to environmental challenges, including those posed by infectious agents.

Metabolic Reprogramming in Host Response

Metabolic pathways are fundamental to every cellular process, including the energetic demands and biosynthesis requirements of an immune response. Cells undergoing activation or stress, such as during an infection, often undergo metabolic reprogramming to support rapid proliferation, effector functions, and repair mechanisms. While direct evidence from the provided context on infectious disease metabolism is not explicit, the principle of metabolic regulation and flux control is universal. These processes, often governed by allosteric control and feedback loops, dictate how efficiently a cell can generate energy (e.g., ATP), synthesize essential molecules (e.g., nucleotides, lipids), or break down waste products. Genetic predispositions can subtly alter the efficiency or responsiveness of these metabolic pathways, potentially impacting the vigor and duration of a host’s defense mechanisms.

Systems-Level Integration and Pathway Crosstalk

Disease often emerges from the systems-level integration of multiple interacting pathways rather than isolated genetic defects. Pathway crosstalk, where different signaling networks influence each other, and broader network interactions define the complex landscape of cellular responses. The discovery of numerous susceptibility loci for complex conditions like Crohn’s disease^[2]and Kawasaki disease^[5]highlights how genetic variations can perturb these intricate networks. Such perturbations can lead to pathway dysregulation, where normal feedback loops are disrupted, or compensatory mechanisms are activated, sometimes with unintended consequences. Understanding these hierarchical regulations and emergent properties is essential for identifying potential therapeutic targets that can modulate the overall disease phenotype.

Natural Selection and Immune System Evolution

Genetic variants influencing the human immune system have been under intense natural selection throughout evolutionary history, primarily driven by the constant co-evolutionary arms race with pathogens. Genes critical for immune defense, such as those related to celiac disease^[4] or implicated in inflammatory bowel diseases (IBD) like Crohn’s ^[11], ^[1], ^[12], ^[3], likely underwent selective sweeps where beneficial alleles rapidly increased in frequency due to their protective effects against prevalent infectious agents. However, some of these variants may also persist due to balancing selection, offering protection against one type of pathogen while potentially increasing susceptibility to others, or conferring an advantage in specific environmental contexts. These dynamic pressures have shaped the complex genetic architecture of our immune responses, leading to both robust defenses and predispositions to inflammatory conditions.

Population Dynamics of Disease Susceptibility Variants

The distribution and frequencies of immune-related genetic variants across human populations are significantly influenced by various population genetic forces. Genetic drift, particularly through historical founder effects and population bottlenecks, has led to substantial variations in allele frequencies among different ancestral groups, impacting present-day disease susceptibility. For instance, the specific immune response variants identified in studies of common diseases^[6]or conditions like Kawasaki disease^[5] may show differential prevalence in geographically distinct populations. Furthermore, patterns of human migration and subsequent admixture events have introduced and redistributed these genetic variants, contributing to the observed global and temporal changes in the prevalence of diseases related to immune function.

Evolutionary Trade-offs and Disease Predisposition

The evolutionary history of genes involved in immune and inflammatory responses often reflects significant trade-offs, where alleles that conferred a fitness advantage in ancestral environments may now contribute to disease predisposition. While certain variants provided crucial benefits for pathogen clearance, particularly against infectious diseases common in earlier human populations, these same genes can have pleiotropic effects. In modern environments, these pleiotropic effects, combined with altered environmental pressures, can lead to maladaptive outcomes such as autoimmune or chronic inflammatory conditions. This highlights evolutionary constraints, where genetic adaptations optimized for past infectious threats may inadvertently increase susceptibility to new health challenges, underscoring the complex interplay between adaptive significance and disease risk.

Frequently Asked Questions About Infectious Disease

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

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1. Why do I catch every bug, but my friend stays healthy?

It’s not just bad luck! Your genetic makeup plays a big role in how your immune system responds to pathogens. Genetic variations can make some people more susceptible or resistant to certain infections, meaning your friend might have a genetic advantage in fighting off common bugs compared to you.

2. Why does my infection get so much worse than others’ who caught the same thing?

Your genes can significantly influence how severe an infection becomes. Even with the same pathogen, individual genetic variations affect the strength and specificity of your immune response, determining whether you experience mild symptoms or a more severe, prolonged illness.

3. If my parents get really sick often, does that mean I will too?

You can inherit genetic predispositions from your parents that influence your immune system’s capabilities. While it doesn’t guarantee you’ll get sick as often, your genetic background can make you more or less susceptible to certain infections and impact how your body fights them off.

4. Does my family’s background affect how I fight infections?

Yes, your ancestral background can play a role. Genetic variations associated with immune responses can differ across populations, meaning certain groups may have different susceptibilities or resistances. Research often needs to account for these population-specific genetic differences.

5. Can my daily habits actually change how sick I get?

Absolutely. Your lifestyle, diet, and other environmental exposures profoundly interact with your genetic predispositions. Even if you have a genetic susceptibility, healthy habits can strengthen your immune system and influence how well you fight off infections.

6. Are some people just naturally resistant to certain germs?

Yes, some individuals are indeed naturally more resistant. Their unique genetic variations can lead to a more effective immune response against specific pathogens, allowing them to fight off an infection without developing symptoms or even becoming infected at all.

7. Could a DNA test tell me which infections I’m most vulnerable to?

Understanding your genetic predispositions could eventually lead to personalized preventive strategies. While current tests have limitations and don’t explain all risk, they can identify some genetic variations that might influence your susceptibility or how your immune system responds to certain pathogens.

8. Why is my sibling rarely sick, but I always am?

Even between siblings, there are unique genetic differences that influence immune function. These variations can lead to one sibling having a more robust or specific immune response to common pathogens, making them appear healthier than another.

9. Why do some prevention methods work better for some people?

Your genetic makeup can influence how effectively your immune system responds to preventive measures, like vaccines. While prevention is crucial for everyone, individual genetic variations mean that some people might mount a stronger protective response than others.

10. Does stress really make me more likely to get sick?

Yes, stress is a significant environmental factor that can impact your immune system. It interacts with your genetic predispositions, potentially weakening your body’s defenses and making you more vulnerable to infections, even if you have a generally strong genetic profile.

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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] Rioux JD et al. “Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis.”Nat Genet, 2009.

[2] Barrett JC et al. “Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease.”Nat Genet, 2009.

[3] Kugathasan S et al. “Loci on 20q13 and 21q22 are associated with pediatric-onset inflammatory bowel disease.”Nat Genet, 2009.

[4] Hunt KA et al. “Newly identified genetic risk variants for celiac disease related to the immune response.”Nat Genet, 2009.

[5] Burgner D et al. “A genome-wide association study identifies novel and functionally related susceptibility Loci for Kawasaki disease.”PLoS Genet, vol. 5, no. 1, 2009, p. e1000319.

[6] Wellcome Trust Case Control Consortium. “Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.” Nature, 2009.

[7] Garcia-Barcelo MM, et al. “Genome-wide association study identifies NRG1 as a susceptibility locus for Hirschsprung’s disease.” Proc Natl Acad Sci U S A. 2009 Feb 10.

[8] Parkes, M., et al. “Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn’s disease susceptibility.”Nat Genet, 2007.

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

[10] Lunetta KL, et al. “Genetic correlates of longevity and selected age-related phenotypes: a genome-wide association study in the Framingham Study.” BMC Med Genet, vol. 8, no. S1, 2007, p. S4.

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

[12] Franke A et al. “Systematic association mapping identifies NELL1 as a novel IBD disease gene.”PLoS One, no. 8, 2007, p. e691.

[13] Reiman, Eric M., et al. “GAB2 alleles modify Alzheimer’s risk in APOE epsilon4 carriers.” Neuron, vol. 54, no. 5, 2007, pp. 713-20.