共查询到20条相似文献，搜索用时 15 毫秒
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Nina Mars Joni V. Lindbohm Pietro della Briotta Parolo Elisabeth Widn Jaakko Kaprio Aarno Palotie FinnGen Samuli Ripatti 《American journal of human genetics》2022,109(12):2152-2162
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Biological aging is associated with a reduction in the reparative and regenerative potential in tissues and organs. This reduction manifests as a decreased physiological reserve in response to stress (termed homeostenosis) and a time‐dependent failure of complex molecular mechanisms that cumulatively create disorder. Aging inevitably occurs with time in all organisms and emerges on a molecular, cellular, organ, and organismal level with genetic, epigenetic, and environmental modulators. Individuals with the same chronological age exhibit differential trajectories of age‐related decline, and it follows that we should assess biological age distinctly from chronological age. In this review, we outline mechanisms of aging with attention to well‐described molecular and cellular hallmarks and discuss physiological changes of aging at the organ‐system level. We suggest methods to measure aging with attention to both molecular biology (e.g., telomere length and epigenetic marks) and physiological function (e.g., lung function and echocardiographic measurements). Finally, we propose a framework to integrate these molecular and physiological data into a composite score that measures biological aging in humans. Understanding the molecular and physiological phenomena that drive the complex and multifactorial processes underlying the variable pace of biological aging in humans will inform how researchers assess and investigate health and disease over the life course. This composite biological age score could be of use to researchers seeking to characterize normal, accelerated, and exceptionally successful aging as well as to assess the effect of interventions aimed at modulating human aging. 相似文献
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Xaquín Gurriarn Julio Rodríguez‐Lpez Gerardo Flrez Csar Pereiro Jos M. Fernndez Emilio Farias Valentín Estvez Manuel Arrojo Javier Costas 《Genes, Brain & Behavior》2019,18(3)
Genetic susceptibility to substance use disorders (SUDs) is partially shared between substances. Heritability of any substance dependence, estimated as 54%, is partly explained by additive effects of common variants. Comorbidity between SUDs and other psychiatric disorders is frequent. The present study aims to analyze the additive role of common variants in this comorbidity using polygenic scores (PGSs) based on genome‐wide association study discovery samples of schizophrenia (SCZ), bipolar disorder, attention‐deficit/hyperactivity disorder, autism spectrum disorder, major depressive disorder and anxiety disorders, available from large consortia. PGSs were calculated for 534 patients meeting DSM‐IV criteria for dependence of a substance and abuse/dependence of another substance between alcohol, tobacco, cannabis, cocaine, opiates, hypnotics, stimulants, hallucinogens and solvents; and 587 blood donors from the same population, Iberians from Galicia, as controls. Significance of the PGS and percentage of variance explained were calculated by logistic regression. Using discovery samples of similar size, significant associations with SUDs were detected for SCZ PGS. SCZ PGS explained more variance in SUDs than in most psychiatric disorders. Cross‐disorder PGS based on five psychiatric disorders was significant after adjustment for the effect of SCZ PGS. SCZ PGS was significantly higher in women than in men abusing alcohol. Our findings indicate that SUDs share genetic susceptibility with SCZ to a greater extent than with other psychiatric disorders, including externalizing disorders such as attention‐deficit/hyperactivity disorder. Women have lower probability to develop substance abuse/dependence than men at similar PGS probably because of a higher social pressure against excessive drug use in women. 相似文献
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多基因遗传风险评分（polygenic risk score,PRS）是一种新兴的遗传数据分析方法。该方法通过对个体多个遗传变异位点的综合考虑,对个体复杂疾病的遗传风险进行定量评估,在遗传学领域受到广泛关注,同时该方法的有效性也在临床应用中得到进一步验证。由于PRS的计算涉及大量的基因组数据分析,其模型的数据选择、构建方法以及验证方法均存在较大差异。本综述结合目前已发表的PRS相关研究和算法,对PRS模型以及其应用进行阐述。 相似文献
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Yannick Stephan Angelina R. Sutin Martina Luchetti Antonio Terracciano 《Genes, Brain & Behavior》2020,19(4)
Neuroticism, a broad trait measure of the tendency to experience negative emotions and vulnerability to stress, is consistently related to poor sleep quality. Less is known about potential pleiotropy in the genetic risk for high neuroticism and poor sleep. Therefore, the present study examined whether polygenic score (PGS) for neuroticism is related to sleep quality in two large samples of adults. In addition, depressive symptoms, anxiety and phenotypical neuroticism were tested as mediators in both samples. Participants were 8316 individuals aged from 50 to 101 years (mean age = 68.29, SD = 9.83) from the Health and Retirement Study, and 4973 individuals aged from 63 to 67 years (mean age = 64.30, SD = 0.68) from the Wisconsin Longitudinal Study. Participants from both samples were genotyped and answered questions on sleep quality. A higher PGS for neuroticism was related to lower sleep quality concurrently and over time in both samples. Anxiety, depressive symptoms and neuroticism mediated these relationships in the two samples. Although effect sizes were small, the present study provides replicable evidence that individuals with a higher genetic predisposition to experience negative emotions and distress are at risk of sleep difficulties. 相似文献
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Clara Correia‐Melo Jodie Birch Edward Fielder Dina Rahmatika Jennifer Taylor James Chapman Anthony Lagnado Bernadette M. Carroll Satomi Miwa Gavin Richardson Diana Jurk Fiona Oakley Jelena Mann Derek A. Mann Viktor I. Korolchuk Joo F. Passos 《Aging cell》2019,18(1)
Increased activation of the major pro‐inflammatory NF‐κB pathway leads to numerous age‐related diseases, including chronic liver disease (CLD). Rapamycin, an inhibitor of mTOR, extends lifespan and healthspan, potentially via suppression of inflammaging, a process which is partially dependent on NF‐κB signalling. However, it is unknown if rapamycin has beneficial effects in the context of compromised NF‐κB signalling, such as that which occurs in several age‐related chronic diseases. In this study, we investigated whether rapamycin could ameliorate age‐associated phenotypes in a mouse model of genetically enhanced NF‐κB activity (nfκb1?/?) characterized by low‐grade chronic inflammation, accelerated aging and CLD. We found that, despite showing no beneficial effects in lifespan and inflammaging, rapamycin reduced frailty and improved long‐term memory, neuromuscular coordination and tissue architecture. Importantly, markers of cellular senescence, a known driver of age‐related pathology, were alleviated in rapamycin‐fed animals. Our results indicate that, in conditions of genetically enhanced NF‐κB, rapamycin delays aging phenotypes and improves healthspan uncoupled from its role as a suppressor of inflammation. 相似文献
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《American journal of human genetics》2022,109(5):857-870
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João Ricardo Sato Claudinei Eduardo Biazoli Ana Paula Arantes Bueno Arthur Caye Pedro Mario Pan Marcos Santoro Jessica Honorato-Mauer Giovanni Abrahão Salum Marcelo Queiroz Hoexter Rodrigo Affonseca Bressan Andrea Parolin Jackowski Euripedes Constantino Miguel Sintia Belangero Luis Augusto Rohde 《Genes, Brain & Behavior》2023,22(2):e12838
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In the era of big data, univariate models have widely been used as a workhorse tool for quickly producing marginal estimators; and this is true even when in a high-dimensional dense setting, in which many features are “true,” but weak signals. Genome-wide association studies (GWAS) epitomize this type of setting. Although the GWAS marginal estimator is popular, it has long been criticized for ignoring the correlation structure of genetic variants (i.e., the linkage disequilibrium [LD] pattern). In this paper, we study the effects of LD pattern on the GWAS marginal estimator and investigate whether or not additionally accounting for the LD can improve the prediction accuracy of complex traits. We consider a general high-dimensional dense setting for GWAS and study a class of ridge-type estimators, including the popular marginal estimator and the best linear unbiased prediction (BLUP) estimator as two special cases. We show that the performance of GWAS marginal estimator depends on the LD pattern through the first three moments of its eigenvalue distribution. Furthermore, we uncover that the relative performance of GWAS marginal and BLUP estimators highly depends on the ratio of GWAS sample size over the number of genetic variants. Particularly, our finding reveals that the marginal estimator can easily become near-optimal within this class when the sample size is relatively small, even though it ignores the LD pattern. On the other hand, BLUP estimator has substantially better performance than the marginal estimator as the sample size increases toward the number of genetic variants, which is typically in millions. Therefore, adjusting for the LD (such as in the BLUP) is most needed when GWAS sample size is large. We illustrate the importance of our results by using the simulated data and real GWAS. 相似文献
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Jia Yan Fazil Aliev Bradley T. Webb Kenneth S. Kendler Vernell S. Williamson Howard J. Edenberg Arpana Agrawal Mark Z. Kos Laura Almasy John I. Nurnberger Marc A. Schuckit John R. Kramer John P. Rice Samuel Kuperman Alison M. Goate Jay A. Tischfield Bernice Porjesz Danielle M. Dick 《Addiction biology》2014,19(4):708-721
Family‐based and genome‐wide association studies (GWAS) of alcohol dependence (AD) have reported numerous associated variants. The clinical validity of these variants for predicting AD compared with family history information has not been reported. Using the Collaborative Study on the Genetics of Alcoholism (COGA) and the Study of Addiction: Genes and Environment (SAGE) GWAS samples, we examined the aggregate impact of multiple single nucleotide polymorphisms (SNPs) on risk prediction. We created genetic sum scores by adding risk alleles associated in discovery samples, and then tested the scores for their ability to discriminate between cases and controls in validation samples. Genetic sum scores were assessed separately for SNPs associated with AD in candidate gene studies and SNPs from GWAS analyses that met varying P‐value thresholds. Candidate gene sum scores did not exhibit significant predictive accuracy. Family history was a better classifier of case‐control status, with a significant area under the receiver operating characteristic curve (AUC) of 0.686 in COGA and 0.614 in SAGE. SNPs that met less stringent P‐value thresholds of 0.01–0.50 in GWAS analyses yielded significant AUC estimates, ranging from mean estimates of 0.549 for SNPs with P < 0.01 to 0.565 for SNPs with P < 0.50. This study suggests that SNPs currently have limited clinical utility, but there is potential for enhanced predictive ability with better understanding of the large number of variants that might contribute to risk. 相似文献
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Intestinal epithelial cells (IECs) serve as both a physical and an antimicrobial barrier against the microbiota, as well as a conduit for signaling between the microbiota and systemic host immunity. As individuals age, the balance between these systems undergoes a myriad of changes due to age‐associated changes to the microbiota, IECs themselves, immunosenescence, and inflammaging. In this review, we discuss emerging data related to age‐associated loss of intestinal barrier integrity and posit that IEC dysfunction may play a central role in propagating age‐associated alterations in microbiota composition and immune homeostasis. 相似文献