ADHD genetic burden associates with older epigenetic age: mediating roles of education, behavioral and sociodemographic factors among older adults.

BACKGROUND: Shortened lifespans are associated with having Attention Deficit Hyperactivity Disorder (ADHD), which is likely mediated by related behavioral and sociodemographic factors that are also associated with accelerated physiological aging. Such factors include exhibiting more depressive symptoms, more cigarette smoking, higher body mass index, lower educational attainment, lower income in adulthood, and more challenges with cognitive processes compared to the general population. A higher polygenic score for ADHD (ADHD-PGS) is associated with having more characteristic features of ADHD. The degree to which (1) the ADHD-PGS associates with an epigenetic biomarker developed to predict accelerated aging and earlier mortality is unknown, as are whether (2) an association would be mediated by behavioral and sociodemographic correlates of ADHD, or (3) an association would be mediated first by educational attainment, then by behavioral and sociodemographic correlates. We evaluated these relationships in a population-based sample from the US Health and Retirement Study, among N = 2311 adults age 50 and older, of European-ancestry, with blood-based epigenetic and genetic data. The ADHD-PGS was calculated from a prior genomewide meta-analysis. Epigenome-wide DNA methylation levels that index biological aging and earlier age of mortality were quantified by a blood-based biomarker called GrimAge. We used a structural equation modeling approach to test associations with single and multi-mediation effects of behavioral and contextual indicators on GrimAge, adjusted for covariates. RESULTS: The ADHD-PGS was significantly and directly associated with GrimAge when adjusting for covariates. In single mediation models, the effect of the ADHD-PGS on GrimAge was partially mediated via smoking, depressive symptoms, and education. In multi-mediation models, the effect of the ADHD-PGS on GrimAge was mediated first through education, then smoking, depressive symptoms, BMI, and income. CONCLUSIONS: Findings have implications for geroscience research in elucidating lifecourse pathways through which ADHD genetic burden and symptoms can alter risks for accelerated aging and shortened lifespans, when indexed by an epigenetic biomarker. More education appears to play a central role in attenuating negative effects on epigenetic aging from behavioral and sociodemographic risk factors related to ADHD. We discuss implications for the potential behavioral and sociodemographic mediators that may attenuate negative biological system effects.

Longitudinal Examination of an Ethnic Paradox of Stress and Mental Health in Older Black and Latinx Adults.

OBJECTIVES: To explain the ethnic paradox of mental health in aging, we evaluated whether Black and Latinx older adults experience (1) fewer depressive symptoms (DepSx), but more physical problems, and (2) greater psychological resilience as a result of life stressors than White older adults. METHODS: DepSx, physical health, and recent stress were obtained biennially from 25,893 older adults (77% White, 15% Black, 9% Latinx) in the U.S. Health and Retirement Study, across 16 years. Psychological resilience, lifetime stress, and discrimination experiences were available for 13,655 individuals. We conducted mixed-effects and linear regression analyses. RESULTS: For Blacks and Latinxs, experiencing more-than-usual stress events was associated with less increase in DepSx compared to Whites, although on average Blacks and Latinxs experience more DepSx. Black adults showed worse physical health than White adults and weaker effects of stress on psychological resilience despite experiencing more stress of all types. Findings were mixed for Latinxs. CONCLUSIONS: Studying effects of time-varying stress on changes in health and multiple stressors on psychological resilience by race/ethnicity elucidates mechanisms for later-age health disparities. CLINICAL IMPLICATIONS: Cross-sectional evaluations of stress and psychological health in a clinical setting may provide incomplete appraisals of health risks for Black and Latinx older Americans.

Mitochondrial DNA variation in Alzheimer's disease reveals a unique microprotein called SHMOOSE.

Mitochondrial DNA variants have previously associated with disease, but the underlying mechanisms have been largely elusive. Here, we report that mitochondrial SNP rs2853499 associated with Alzheimer's disease (AD), neuroimaging, and transcriptomics. We mapped rs2853499 to a novel mitochondrial small open reading frame called SHMOOSE with microprotein encoding potential. Indeed, we detected two unique SHMOOSE-derived peptide fragments in mitochondria by using mass spectrometry-the first unique mass spectrometry-based detection of a mitochondrial-encoded microprotein to date. Furthermore, cerebrospinal fluid (CSF) SHMOOSE levels in humans correlated with age, CSF tau, and brain white matter volume. We followed up on these genetic and biochemical findings by carrying out a series of functional experiments. SHMOOSE acted on the brain following intracerebroventricular administration, differentiated mitochondrial gene expression in multiple models, localized to mitochondria, bound the inner mitochondrial membrane protein mitofilin, and boosted mitochondrial oxygen consumption. Altogether, SHMOOSE has vast implications for the fields of neurobiology, Alzheimer's disease, and microproteins.

The mitochondrial-derived peptide MOTS-c is a regulator of plasma metabolites and enhances insulin sensitivity.

MOTS-c is an exercise mimetic and improves insulin sensitivity in aged and diet-induced obese mice. Although plasma markers are good markers for the metabolic condition, whether MOTS-c changes plasma markers in diet-induced obese mice has not been examined. Here, we used an unbiased metabolomics approach to examine the effect of MOTS-c on plasma markers of metabolic dysfunction. We found that three pathways - sphingolipid metabolism, monoacylglycerol metabolism, and dicarboxylate metabolism - were reduced in MOTS-c-injected mice. Interestingly, these pathways are upregulated in obese and T2D models. MOTS-c improves insulin sensitivity and increases beta-oxidation to prevent fat accumulation in DIO mice through these pathways. These results provide us a better understanding of the mechanism of how MOTS-c improves insulin sensitivity and reduces the body weight and fatty liver and opens a new venue for further study.

Neuropsychological Test Performance and MRI Markers of Dementia Risk: Reducing Education Bias.

BACKGROUND: To use neuropsychological assessments for studying the underlying disease processes contributing to dementia, it is crucial that they correspond to magnetic resonance imaging (MRI)-based measures of dementia, regardless of educational level. METHODS: French 3-City Dijon MRI study cohort members (n=1782) with assessments of white matter lesion volume (WMLV), hippocampal volume (HCV), and cerebrospinal fluid volume (CSFV), and 6 waves of neuropsychological assessments over 11 years, including Mini-Mental State Examination (MMSE), plus 5 other tests combined using a Z-score or item-response theory (IRT-cognition) comprised the study cohort. We evaluated, testing interactions, whether education modified associations of MRI markers with intercept or rate of change of MMSE, Z-score composite, or IRT-cognition. RESULTS: In linear models, education modified the associations of WMLV and CSFV with MMSE and CSFV and Z-score composite. In mixed models, education modified the associations of WMLV and CSFV with level of MMSE and the association of HCV with slope of MMSE. Education also modified the association with CSFV and slope of Z-score composite decline. There was no evidence that education modified associations between MRI measures and level or slope of IRT-cognition. CONCLUSIONS: Longitudinal analysis of correctly scaled neuropsychological assessments may provide unbiased proxies for MRI-based measures of dementia risk.

Comparing the Utility of Mitochondrial and Nuclear DNA to Adjust for Genetic Ancestry in Association Studies.

Mitochondrial genome-wide association studies identify mitochondrial single nucleotide polymorphisms (mtSNPs) that associate with disease or disease-related phenotypes. Most mitochondrial and nuclear genome-wide association studies adjust for genetic ancestry by including principal components derived from nuclear DNA, but not from mitochondrial DNA, as covariates in statistical regression analyses. Furthermore, there is no standard when controlling for genetic ancestry during mitochondrial and nuclear genetic interaction association scans, especially across ethnicities with substantial mitochondrial genetic heterogeneity. The purpose of this study is to (1) compare the degree of ethnic variation captured by principal components calculated from microarray-defined nuclear and mitochondrial DNA and (2) assess the utility of mitochondrial principal components for association studies. Analytic techniques used in this study include a principal component analysis for genetic ancestry, decision-tree classification for self-reported ethnicity, and linear regression for association tests. Data from the Health and Retirement Study, which includes self-reported White, Black, and Hispanic Americans, was used for all analyses. We report that (1) mitochondrial principal component analysis (PCA) captures ethnic variation to a similar or slightly greater degree than nuclear PCA in Blacks and Hispanics, (2) nuclear and mitochondrial DNA classify self-reported ethnicity to a high degree but with a similar level of error, and 3) mitochondrial principal components can be used as covariates to adjust for population stratification in association studies with complex traits, as demonstrated by our analysis of height-a phenotype with a high heritability. Overall, genetic association studies might reveal true and robust mtSNP associations when including mitochondrial principal components as regression covariates.

Frailty Index associates with GRIN2B in two representative samples from the United States and the United Kingdom.

The concept of frailty has been used in the clinical and research field for more than two decades. It is usually described as a clinical state of heightened vulnerability to poor resolution of homeostasis after a stressor event, which thereby increases the risk of adverse outcomes, including falls, delirium, disability and mortality. Here we report the results of the first genome-wide association scan and comparative gene ontology analyses where we aimed to identify genes and pathways associated with the deficit model of frailty. We used a discovery-replication design with two independent, nationally representative samples of older adults. The square-root transformed Frailty Index (FI) was the outcome variable, and age and sex were included as covariates. We report one hit exceeding genome-wide significance: the rs6765037 A allele was significantly associated with a decrease in the square-root transformed FI score in the Discovery sample (beta = -0.01958, p = 2.14E-08), without confirmation in the Replication sample. We also report a nominal replication: the rs7134291 A allele was significantly associated with a decrease in the square-root transformed FI score (Discovery sample: beta = -0.01021, p = 1.85E-06, Replication sample: beta = -0.005013, p = 0.03433). These hits represent the KBTBD12 and the GRIN2B genes, respectively. Comparative gene ontology analysis identified the pathways 'Neuropathic pain signalling in dorsal horn neurons' and the 'GPCR-Mediated Nutrient Sensing in Enteroendocrine Cells', exceeding the p = 0.01 significance in both samples, although this result does not survive correction for multiple testing. Considering the crucial role of GRIN2B in brain development, synaptic plasticity and cognition, this gene appears to be a potential candidate to play a role in frailty. In conclusion, we conducted genome-wide association scan and pathway analyses and have identified genes and pathways with potential roles in frailty. However, frailty is a complex condition. Therefore, further research is required to confirm our results and more thoroughly identify relevant biological mechanisms.

Genome-wide scan of depressive symptomatology in two representative cohorts in the United States and the United Kingdom.

Unlike the diagnosed Major Depressive Disorder, depressive symptomatology in the general population has received less attention in genome-wide association scan (GWAS) studies. Here we report a GWAS study on depressive symptomatology using a discovery-replication design and the following approaches: To improve the robustness of the phenotypic measure, we used longitudinal data and calculated mean scores for at least 3 observations for each individual. To maximize replicability, we used nearly identical genotyping platforms and identically constructed phenotypic measures in both the Discovery and Replication samples. We report one genome-wide significant hit; rs58682566 in the EPG5 gene was associated (p = 3.25E-08) with the mean of the depression symptom in the Discovery sample, without confirmation in the Replication sample. We also report 4 hits exceeding the genome-wide suggestive significance level with nominal replications. Rs11774887, rs4147527 and rs1379328, close to the SAMD12 gene, were associated with the mean depression symptom score (P-values in Discovery sample: 4.58E-06, 7.65E-06 and 7.66E-06; Replication sample: 0.049, 0.029 and 0.030, respectively). Rs13250896, located in an intergenic region, was associated with the mean score of the three somatic items of the depression symptoms score (p = 3.31E-07 and 0.042 for the Discovery and Replication samples). These results were not supported by evidence in the literature. We conclude that despite the strengths of our approach, using robust phenotypic measures and samples that maximize replicability potential, this study does not provide compelling evidence of a single genetic variant's significant role in depressive symptomatology.

Genetic variants specific to aging-related verbal memory: Insights from GWASs in a population-based cohort.

Verbal memory is typically studied using immediate recall (IR) and delayed recall (DR) scores, although DR is dependent on IR capability. Separating these components may be useful for deciphering the genetic variation in age-related memory abilities. This study was conducted to (a) construct individual trajectories in IR and independent aspects of delayed recall, or residualized-DR (rDR), across older adulthood; and (b) identify genetic markers that contribute to four estimated phenotypes: IR and rDR levels and changes after age 60. A cognitively intact sample (N = 20,650 with 125,164 observations) was drawn from the U.S. Health and Retirement Study, a nationally representative study of adults aged 50 and older. Mixed effects regression models were constructed using repeated measures from data collected every two years (1996-2012) to estimate level at age 60 and change in memory post-60 in IR and rDR. Genome-wide association scans (GWAS) were conducted in the genotypic subsample (N = 7,486) using ~1.2 million single nucleotide polymorphisms (SNPs). One SNP (rs2075650) in TOMM40 associated with rDR level at the genome-wide level (p = 5.0x10-08), an effect that replicated in an independent sample from the English Longitudinal Study on Ageing (N = 6,898 with 41,328 observations). Meta-analysis of rDR level confirmed the association (p = 5.0x10-11) and identified two others in TOMM40 (rs71352238 p = 1.0x10-10; rs157582 p = 7.0x10-09), and one in APOE (rs769449 p = 3.1 x10-12). Meta-analysis of IR change identified associations with three of the same SNPs in TOMM40 (rs157582 p = 8.3x10-10; rs71352238 p = 1.9x10-09) and APOE (rs769449 p = 2.2x10-08). Conditional analyses indicate GWAS signals on rDR level were driven by APOE, whereas signals on IR change were driven by TOMM40. Additionally, we found that TOMM40 had effects independent of APOE e4 on both phenotypes. Findings from this first U.S. population-based GWAS study conducted on both age-related immediate and delayed verbal memory merit continued examination in other samples and additional measures of verbal memory.

Effects of Recent Stress and Variation in the Serotonin Transporter Polymorphism (5-HTTLPR) on Depressive Symptoms: A Repeated-Measures Study of Adults Age 50 and Older.

Depending on genetic sensitivity to it, stress may affect depressive symptomatology differentially. Applying the stress-diathesis hypothesis to older adults, we postulate: (1) recent stress will associate with increased depressive symptom levels and (2) this effect will be greater for individuals with at least one short allele of the serotonin transporter gene promoter region (5-HTTLPR). Further, we employ a design that addresses specific limitations of many prior studies that have examined the 5-HTTLPR × SLE relation, by: (a) using a within-person repeated-measures design to address fluctuations that occur within individuals over time, increase power for detecting G × E, and address GE correlation; (b) studying reports of exogenous stressful events (those unlikely to be caused by depression) to help rule out reverse causation and negativity bias, and in order to assess stressors that are more etiologically relevant to depressive symptomatology in older adults. The sample is drawn from the Health and Retirement Study, a U.S. population-based study of older individuals (N = 28,248; mean age = 67.5; 57.3 % female; 80.7 % Non-Hispanic White, 14.9 % Hispanic/Latino, 4.5 % African American; genetic subsample = 12,332), from whom measures of depressive symptoms and exogenous stressors were collected biannually (1994-2010). Variation in the 5-HTTLPR was characterized via haplotype, using two single nucleotide polymorphisms (SNPs). Ordered logit models were constructed to predict levels of depressive symptoms from 5-HTTLPR and stressors, comparing results of the most commonly applied statistical approaches (i.e., comparing allelic and genotypic models, and continuous and categorical predictors) used in the literature. All models were stratified by race/ethnicity. Overall, results show a main effect of recent stress for all ethnic groups, and mixed results for the variation in 5-HTTLPR × stress interaction, contingent upon statistical model used. Findings suggest there may be a differential effect of stressors and 5-HTTLPR on depressive symptoms by ethnicity, but further research is needed, particularly when using a haplotype to characterize variation in 5-HTTLPR in population-based sample with a diverse ethnic composition.

Stressful Life Events and Predictors of Post-traumatic Growth among High-Risk Early Emerging Adults.

Stressful life events (SLEs) may elicit positive psychosocial change among youth, referred to as Post-traumatic Growth (PTG). We assessed types of SLEs experienced, degree to which participants reported PTG, and variables predicting PTG across 24 months among a sample of high risk, ethnically diverse early emerging adults. Participants were recruited from alternative high schools (n = 564; mean age=16.8; 65% Hispanic). Multi-level regression models were constructed to examine the impact of environmental (SLE quantity, severity) and personal factors (hedonic ability, perceived stress, developmental stage, future time orientation) on a composite score of PTG. The majority of participants reported positive changes resulted from their most life-altering SLE of the past two years. Predictors of PTG included fewer SLEs, less general stress, having a future time perspective, and greater identification with the developmental stage of Emerging Adulthood. Findings suggest intervention targets to foster positive adaptation among early emerging adults who experience frequent SLEs.

Post-traumatic growth, stressful life events, and relationships with substance use behaviors among alternative high school students: a prospective study.

A highly stressful life event (SLE) can elicit positive psychosocial growth, referred to as post-traumatic growth (PTG) among youth. We examined PTG and the number of SLEs for their influence on substance use behaviours among a sample of older, diverse alternative high school students participating in a drug prevention programme (n=564; mean age=16.8; 49% female; 65% Hispanic). Surveys assessed PTG, SLEs and substance use behaviours at the two-year follow-up. Multilevel regression models were run to examine the effect of PTG and the number of SLEs on frequency of substance use at the two-year follow-up, controlling for baseline substance use, sociodemographic variables, peer substance use, attrition propensity and treatment group. Greater PTG scores were associated with lower frequencies of alcohol use, getting drunk on alcohol, binge drinking, marijuana use and less substance abuse at the two-year follow-up, but not associated with cigarette or hard drug use. Also, PTG did not moderate the relationship between cumulative number of SLEs and substance use behaviours, rather PTG appears to be protective against negative effects of a single, life-altering SLE. Fostering PTG from a particularly poignant SLE may be useful for prevention programmes targeting alcohol, marijuana and substance abuse behaviours among high-risk youth.

A polygenic risk score associated with measures of depressive symptoms among older adults.

It has been suggested that depression is a polygenic trait, arising from the influences of multiple loci with small individual effects. The aim of this study is to generate a polygenic risk score (PRS) to examine the association between genetic variation and depressive symptoms. Our analytic sample included N = 10,091 participants aged 50 and older from the Health and Retirement Study (HRS). Depressive symptoms were measured by Center for Epidemiological Studies-Depression scale (CESD) scores assessed on up to nine occasions across 18 years. We conducted a genome-wide association analysis for a discovery set (n = 7,000) and used the top 11 single-nucleotide polymorphisms, all with p < 10(-5) to generate a weighted PRS for our replication sample (n = 3,091). Results showed that the PRS was significantly associated with mean CESD score in the replication sample (ß = .08, p = .002). The R(2) change for the inclusion of the PRS was .003. Using a multinomial logistic regression model, we also examined the association between genetic risk and chronicity of high (4+) CESD scores. We found that a one-standard-deviation increase in PRS was associated with a 36 percent increase in the odds of having chronically high CESD scores relative to never having had high CESD scores. Our findings are consistent with depression being a polygenic trait and suggest that the cumulative influence of multiple variants increases an individual's susceptibility for chronically experiencing high levels of depressive symptoms.

Spirituality in addictions treatment: wisdom to know what it is.

Spirituality has long been integrated into treatments for addiction. However, how spirituality differs from other related constructs and implications for recovery among nonspiritual persons remains a source of discussion. This article examines ways in which spirituality is delineated, identifies variables that might mediate the relations between spirituality and recovery from substance abuse disorders, describes distinctions between spiritual and nonspiritual facets of addictions treatment, and suggests means to assist in further clarification of this construct.

Concurrent and predictive relationships between compulsive internet use and substance use: findings from vocational high school students in China and the USA.

PURPOSE: Compulsive Internet Use (CIU) has increasingly become an area of research among process addictions. Largely based on data from cross-sectional studies, a positive association between CIU and substance use has previously been reported. This study presents gender and country-specific longitudinal findings on the relationships between CIU and substance use. METHODS: Data were drawn from youth attending non-conventional high schools, recruited into two similarly implemented trials conducted in China and the USA. The Chinese sample included 1,761 students (49% male); the US sample included 1,182 students (57% male) with over half (65%) of the US youth being of Hispanic ethnicity. Path analyses were applied to detect the concurrent and predictive relationships between baseline and one-year follow-up measures of CIU level, 30-day cigarette smoking, and 30-day binge drinking. RESULTS: (1) CIU was not positively related with substance use at baseline. (2) There was a positive predictive relationship between baseline CIU and change in substance use among female, but not male students. (3) Relationships between concurrent changes in CIU and substance use were also found among female, but not male students. (4) Baseline substance use did not predict an increase in CIU from baseline to 1-year follow-up. CONCLUSIONS: While CIU was found to be related to substance use, the relationship was not consistently positive. More longitudinal studies with better measures for Internet Addiction are needed to ascertain the detailed relationship between Internet addiction and substance use.