Analysis of 589,306 genomes identifies individuals resilient to severe Mendelian childhood diseases

Chen, Rong; Shi, Lisong; Hakenberg, Jörg; Naughton, Brian; Sklar, Pamela; Zhang, Shiping; Zhou, Hanlin; Tian, Lifeng; Prakash, Om; Lemire, Mathieu; Sleiman, Patrick; Cheng, Wei‐Yi; Chen, Wanting; Shah, Hardik; Shen, Yulan; Fromer, Menachem; Omberg, Larsson; Deardorff, Matthew A.; Zackai, Elaine H.; Bobe, Jason; Levin, Elissa; Hudson, Thomas J.; Groop, Leif; Wang, Jun; Hákonarson, Hákon; Wojcicki, Anne; Diaz, George A.; Edelmann, Lisa; Schadt, Eric E.; Friend, Stephen H.

doi:10.1038/nbt.3514

Cited by 277 publications

(265 citation statements)

References 57 publications

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“…Similarly, genes involved in predisposition to rheumatoid arthritis ( CTLA4 and IL6R ) are targets for drugs used to treat rheumatoid arthritis as well as other autoimmune diseases. There is also increasing interest in utilizing genetic studies to identify individuals with protective genetic variants that might inform drug target identification (Chen et al, 2016; Erikson et al, 2016). For example, rare loss-of-function mutations in a zinc transporter ( SLC30A8 ) were found to be protective against type 2 diabetes and thus thought to be indicative of a novel diabetes treatment strategy (Flannick et al, 2014).…”

Section: High Precision Treatmentmentioning

confidence: 99%

High-Definition Medicine

Torkamani

Andersen

Steinhubl

et al. 2017

Cell

183

139

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The foundation for a new era of data-driven medicine has been set by recent technological advances that enable the assessment and management of human health at an unprecedented level of resolution – what we refer to as high definition medicine. Our ability to assess human health in high definition is enabled, in part, by advances in DNA sequencing, physiological and environmental monitoring, advanced imaging and behavioral tracking. Our ability to understand and act upon these observations at equally high precision is driven by advances in genome editing, cellular reprogramming, tissue engineering, and information technologies, especially artificial intelligence. In this review, we will examine the core disciplines that enable high definition medicine, and project how these technologies will alter the future of medicine.

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Section: High Precision Treatmentmentioning

confidence: 99%

High-Definition Medicine

Torkamani

Andersen

Steinhubl

et al. 2017

Cell

183

139

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“…According to the authors of this paper, Census-based datasets of aged individuals with comprehensive phenotyping are invaluable resource toward the improved understanding of variant pathogenicity. A few recent publications which supported the above mentioned investigation is cited below (CHEN et al, 2016;DEWEY et al, 2015;FERNANDES et al, 2016;HENN et al, 2015;LEK et al, 2016).…”

Section: The Diagram Inmentioning

confidence: 71%

Healthy human aging: intrinsic and environmental factors

Sgarbieri

Pacheco

2017

Braz. J. Food Technol.

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This review is an attempt to compile current knowledge on concepts and transformations that occur naturally in the human body and that characterize what is defined today as biological aging with quality of life and longevity. Many authors define natural aging as a continuous and uninterrupted process, which occurs in the human body causing structural and functional changes, classified as: cumulative, progressive, intrinsic and deleterious (CUPID). Usually these changes begin early in life and culminate in physical death. Genetic, chemical and biochemical changes lead to progressive degeneration of cells, tissues and organs, body systems and the organism as a whole, leading to loss of structures and functions due to aging. All these changes were discussed in some detail in the review here presented. We concluded that aging is not genetically determined, resulting in the accumulation of cellular and tissue damage, particularly in chromatin and DNA within cells, in addition to structural and bioactive proteins that command the general metabolism. Environmental factors such as feeding (nutrition) and lifestyle were also discussed. Keywords: Biological aging; CUPID; Natural aging; Progressive degeneration. ResumoEsta revisão é uma tentativa de compilação do conhecimento atual sobre conceitos e transformações que ocorrem naturalmente no corpo humano e que caracterizam o que se define, hoje, como envelhecimento biológico saudável, com qualidade de vida e longevidade. Vários autores definem envelhecimento natural como um processo contínuo e ininterrupto, que ocorre no corpo humano provocando mudanças estruturais e funcionais, qualificadas como cumulativas, progressivas, intrínsecas e deletérias (CUPID). Normalmente, essas alterações começam muito cedo na vida e culminam na morte física. Mudanças de natureza genética, química e bioquímica conduzem a degradações progressivas das células, dos tecidos e órgãos, dos sistemas e do organismo como um todo, promovendo, com a idade, perdas de estruturas e funções. Todas estas alterações foram discutidas, em algum detalhe, ao longo da revisão apresentada. Concluiu-se que o envelhecimento não é geneticamente programado, resultando no acúmulo de danos celulares e teciduais, particularmente na cromatina e no DNA, no interior das células, e nas proteínas estruturais e bioativas, que comandam o metabolismo geral. Fatores ambientais, como alimentação (nutrição) e estilo de vida, também foram discutidos. Alimentos, Av. Brasil, 2880, Jardim Chapadão, Caixa Postal: 139, CEP: 13070-178, Campinas/SP -Brazil, e-mail: mtb@ital.sp.gov.br Cite as: Healthy human aging: intrinsic and environmental factors. Braz. Palavras

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“…Screening for 874 distinct Mendelian disease-causing mutations across 589,306 genomes, Chen and colleagues identified 13 asymptomatic adults carrying disease alleles. 57 The low frequency of resilient individuals detected in this study results partly from the strict experimental parameters used. Mutations were selected for the screen based on their extreme rarity in the general population, induction of severe childhood conditions unlikely to be misdiagnosed, and prior clinical annotation of complete disease penetrance.…”

Section: Modifiers Of Complex Traitsmentioning

confidence: 99%

From Peas to Disease: Modifier Genes, Network Resilience, and the Genetics of Health

Riordan

Nadeau

2017

The American Journal of Human Genetics

113

107

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Phenotypes are rarely consistent across genetic backgrounds and environments, but instead vary in many ways depending on allelic variants, unlinked genes, epigenetic factors, and environmental exposures. In the extreme, individuals carrying the same causal DNA sequence variant but on different backgrounds can be classified as having distinct conditions. Similarly, some individuals that carry disease alleles are nevertheless healthy despite affected family members in the same environment. These genetic background effects often result from the action of so-called ''modifier genes'' that modulate the phenotypic manifestation of target genes in an epistatic manner. While complicating the prospects for gene discovery and the feasibility of mechanistic studies, such effects are opportunities to gain a deeper understanding of gene interaction networks that provide organismal form and function as well as resilience to perturbation. Here, we review the principles of modifier genetics and assess progress in studies of modifier genes and their targets in both simple and complex traits. We propose that modifier effects emerge from gene interaction networks whose structure and function vary with genetic background and argue that these effects can be exploited as safe and effective ways to prevent, stabilize, and reverse disease and dysfunction.

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Analysis of 589,306 genomes identifies individuals resilient to severe Mendelian childhood diseases

Cited by 277 publications

References 57 publications

High-Definition Medicine

High-Definition Medicine

Healthy human aging: intrinsic and environmental factors

From Peas to Disease: Modifier Genes, Network Resilience, and the Genetics of Health

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