Mid-to-Late Life Healthy Lifestyle Modifies Genetic Risk for Longitudinal Cognitive Aging among Asymptomatic Individuals.

IMPORTANCE: Genetic and lifestyle factors contribute to an individual's risk of developing Alzheimer's disease. However, it is unknown whether and how adherence to healthy lifestyles can mitigate the genetic risk of Alzheimer's. OBJECTIVE: The aim of this study is to investigate whether adherence to healthy lifestyles can modify the impact of genetic predisposition to Alzheimer's disease on later-life cognitive decline. DESIGN SETTING AND PARTICIPANTS: This prospective cohort study included 891 adults of European ancestry, aged 40 to 65, who were without dementia and had complete healthy-lifestyle and cognition data during the follow-up. Participants joined the Wisconsin Registry for Alzheimer's Prevention (WRAP) beginning in 2001. We conducted replication analyses using a subsample with similar baseline age range from the Health and Retirement Study (HRS). EXPOSURES: We assessed participants' exposures using a continuous non-APOE polygenic risk score for Alzheimer's, a binary indicator for APOE-ε4 carrier status, and a weighted healthy-lifestyle score, including factors such as no current smoking, regular physical activity, healthy diet, light to moderate alcohol consumption, and frequent cognitive activities. MAIN OUTCOMES AND MEASURES: We z-standardized cognitive scores for global (Preclinical Alzheimer's Cognitive Composite score 3 - PACC3) and domain-specific assessments (delayed recall and immediate learning). RESULTS: We followed 891 individuals for up to 10 years (mean [SD] baseline age, 58 [6] years, 31% male, 38% APOE-ε4 carriers). After false discovery rate (FDR) correction, we found statistically significant PRS × lifestyle × age interactions on preclinical cognitive decline but the evidence is stronger among APOE-ε4 carriers. Among APOE-ε4 carriers, PRS-related differences in overall and memory-related domains between people scoring 0-1 and 4-5 regarding healthy lifestyles became evident around age 67 after FDR correction. These findings were robust across several sensitivity analyses and were replicated in the population-based HRS. CONCLUSION: A favorable lifestyle can mitigate the genetic risk associated with current known non-APOE genetic variants for longitudinal cognitive decline, and these protective effects are particularly pronounced among APOE-ε4 carriers.

Vitamin D status and variable responses to supplements depend in part on genetic factors in adults with cystic fibrosis.

Vitamin D sufficiency has been difficult to achieve consistently in patients with cystic fibrosis (CF), even with robust oral supplements. To assess vitamin D status and resistance to supplementation, we studied 80 adults using 25-hydroxyvitamin D (25OHD) determinations and whole genome sequencing to construct polygenic risk scores (PRS) that aggregate variants associated with vitamin D status. The results revealed that 30 % of patients were below the threshold of 30 ng/mL and thus should be regarded as insufficient despite normal vitamin E status, a reflection of adherence to fat soluble vitamin supplementation. The PRS values were significantly correlated with 25OHD concentrations, confirming our results in children with CF, and indicating that genetic factors play a role and have implications for therapy.

CSF metabolites associated with biomarkers of Alzheimer's disease pathology.

Introduction: Metabolomics technology facilitates studying associations between small molecules and disease processes. Correlating metabolites in cerebrospinal fluid (CSF) with Alzheimer's disease (AD) CSF biomarkers may elucidate additional changes that are associated with early AD pathology and enhance our knowledge of the disease. Methods: The relative abundance of untargeted metabolites was assessed in 161 individuals from the Wisconsin Registry for Alzheimer's Prevention. A metabolome-wide association study (MWAS) was conducted between 269 CSF metabolites and protein biomarkers reflecting brain amyloidosis, tau pathology, neuronal and synaptic degeneration, and astrocyte or microglial activation and neuroinflammation. Linear mixed-effects regression analyses were performed with random intercepts for sample relatedness and repeated measurements and fixed effects for age, sex, and years of education. The metabolome-wide significance was determined by a false discovery rate threshold of 0.05. The significant metabolites were replicated in 154 independent individuals from then Wisconsin Alzheimer's Disease Research Center. Mendelian randomization was performed using genome-wide significant single nucleotide polymorphisms from a CSF metabolites genome-wide association study. Results: Metabolome-wide association study results showed several significantly associated metabolites for all the biomarkers except Aß42/40 and IL-6. Genetic variants associated with metabolites and Mendelian randomization analysis provided evidence for a causal association of metabolites for soluble triggering receptor expressed on myeloid cells 2 (sTREM2), amyloid ß (Aß40), α-synuclein, total tau, phosphorylated tau, and neurogranin, for example, palmitoyl sphingomyelin (d18:1/16:0) for sTREM2, and erythritol for Aß40 and α-synuclein. Discussion: This study provides evidence that CSF metabolites are associated with AD-related pathology, and many of these associations may be causal.

Impact of intrinsic and extrinsic risk factors on early-onset lung disease in cystic fibrosis.

BACKGROUND: Although respiratory pathology is known to develop in young children with cystic fibrosis (CF), the determinants of early-onset lung disease have not been elucidated. OBJECTIVE: We aimed to determine the impact of potential intrinsic and extrinsic risk factors during the first 3 years of life, testing the hypothesis that both contribute significantly to early-onset CF lung disease. DESIGN: We studied 104 infants born during 2012-2017, diagnosed through newborn screening by age 3 months, and evaluated comprehensively to 36 months of age. Lung disease manifestations were quantified with a new scoring system known as CFELD for Cystic Fibrosis Early-onset Lung Disease. The variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene were determined and categorized. Whole genome sequencing was performed on each subject and the data transformed to polygenic risk scores (PRS) that aggregate variants associated with lung function. Extrinsic factors included socioeconomic status (SES) indicators and environmental experiences such as exposures to smoking, pets, and daycare. RESULTS: We found by univariate analysis that CFTR genotype and genetic modifiers aggregated by the PRS method were significantly associated with early-onset CF lung disease. Ordinal logistic regression analysis demonstrated that high and stable SES (maternal education ≥community college, stable 2-parent home, and not receiving Medicaid) and better growth (weight-for-age and height-for-age z-scores) reduced risks, while exposure to smoking and daycare ≥20 h/week increased the risk of CFELD severity. CONCLUSIONS: Extrinsic, modifiable determinants are influential early and potentially as important as the intrinsic risk factors in the onset of CF lung disease.

Identification of plasma metabolites associated with modifiable risk factors and endophenotypes reflecting Alzheimer's disease pathology.

Modifiable factors can influence the risk for Alzheimer's disease (AD) and serve as targets for intervention; however, the biological mechanisms linking these factors to AD are unknown. This study aims to identify plasma metabolites associated with modifiable factors for AD, including MIND diet, physical activity, smoking, and caffeine intake, and test their association with AD endophenotypes to identify their potential roles in pathophysiological mechanisms. The association between each of the 757 plasma metabolites and four modifiable factors was tested in the wisconsin registry for Alzheimer's prevention cohort of initially cognitively unimpaired, asymptomatic middle-aged adults. After Bonferroni correction, the significant plasma metabolites were tested for association with each of the AD endophenotypes, including twelve cerebrospinal fluid (CSF) biomarkers, reflecting key pathophysiologies for AD, and four cognitive composite scores. Finally, causal mediation analyses were conducted to evaluate possible mediation effects. Analyses were performed using linear mixed-effects regression. A total of 27, 3, 23, and 24 metabolites were associated with MIND diet, physical activity, smoking, and caffeine intake, respectively. Potential mediation effects include beta-cryptoxanthin in the association between MIND diet and preclinical Alzheimer cognitive composite score, hippurate between MIND diet and immediate learning, glutamate between physical activity and CSF neurofilament light, and beta-cryptoxanthin between smoking and immediate learning. Our study identified several plasma metabolites that are associated with modifiable factors. These metabolites can be employed as biomarkers for tracking these factors, and they provide a potential biological pathway of how modifiable factors influence the human body and AD risk.

Genetic factors help explain the variable responses of young children with cystic fibrosis to vitamin D supplements.

BACKGROUND & AIMS: Children with cystic fibrosis (CF) are susceptible to fat-soluble vitamin deficiencies unless supplemented, but even large doses of vitamin D may not prevent low 25-hydroxyvitamin D (25OHD) concentrations. The explanation for these vitamin D non-responders has been elusive. We utilized data from whole genome sequencing (WGS) to test the hypothesis that genetic variations predict responsiveness to vitamin D supplementation in a prospective cohort study of children with CF in the first 3 years of life. METHODS: One hundred and one infants born during 2012-2017 and diagnosed with CF through newborn screening were studied. Serum 25OHD concentrations and vitamin D supplement doses were assessed during early infancy and annually thereafter. WGS was performed, the resultant variant calling files processed, and the summary statistics from a recent genome-wide association study were utilized to construct a polygenic risk score (PRS) for each subject. RESULTS: Overall, the prevalence of vitamin D insufficiency (<30 ng/mL) was 21% in the first 3 years of life. Among the 70 subjects who always adhered to vitamin D supplement doses recommended by the US CF Foundation guidelines, 89% were responders (achieved vitamin D sufficiency) by 3 years of age, while 11% were transient or non-responders. Multiple regression analysis revealed that PRS was a significant predictor of 25OHD concentrations (p < 0.001) and the likelihood of being an earlier responder in the first 3 years of life (p < 0.01). A limited SNP analysis revealed variants in four important genes (GC, LIPC, CYP24A1, and PDE3B) that were shown to be associated with 25OHD concentrations and vitamin D responder status. Other determinants included vitamin D supplement dose, season at 25OHD measurement, and pancreatic functional status. CONCLUSIONS: Applying WGS in conjunction with utilizing a PRS approach revealed genetic variations that partially explain the unresponsiveness of some children with CF to vitamin D supplementation. Our findings suggest that a nutrigenomics strategy could help promote personalized treatment in CF.

Gene-by-peer-environment interaction effects on cigarette, alcohol, and marijuana use among US high school students of European Ancestry.

Research has shown that adolescents' substance use behavior is determined not only by individual characteristics but also by peer environments, and an emerging literature in social genomics has also found that individual genotypes moderate peer effects on egos' substance use. However, the previous literature on genetic by peer environment (GxPE) interaction effects is limited by the use of genetic measures with limited power and a lack of focus on causality. Based on a sample of about 4000 adolescents of European Ancestry from the National Longitudinal Study of Adolescent to Adult Health, this study utilizes polygenic scores to examine GxPE interactions between ego's genetics and peers' cigarette, alcohol, and marijuana use. The results show peers' cigarette and marijuana use positively affect ego's substance use, and peer effects are stronger when the ego is genetically predisposed to substance use. However, genetic propensities toward risk tolerance are found to weaken the peer effects on the ego's marijuana use. Overall, our findings provide new evidence for the existence of GxPE effects on adolescent substance use and reveal the multidimensional nature of GxPE effects.

The Socioeconomic Gradient in Epigenetic Ageing Clocks: Evidence from the Multi-Ethnic Study of Atherosclerosis and the Health and Retirement Study.

Epigenetic clocks have been widely used to predict disease risk in multiple tissues or cells. Their success as a measure of biological ageing has prompted research on the connection between epigenetic pathways of ageing and the socioeconomic gradient in health and mortality. However, studies examining social correlates of epigenetic ageing have yielded inconsistent results. We conducted a comprehensive, comparative analysis of associations between various dimensions of socioeconomic status (SES) (education, income, wealth, occupation, neighbourhood environment, and childhood SES) and eight epigenetic clocks in two well-powered US ageing studies: The Multi-Ethnic Study of Atherosclerosis (MESA) (n = 1,211) and the Health and Retirement Study (HRS) (n = 4,018). In both studies, we found robust associations between SES measures in adulthood and the GrimAge and DunedinPoAm clocks (Bonferroni-corrected p-value < 0.01). In the HRS, significant associations with the Levine and Yang clocks were also evident. These associations were only partially mediated by smoking, alcohol consumption, and obesity, which suggests that differences in health behaviours alone cannot explain the SES gradient in epigenetic ageing in older adults. Further analyses revealed concurrent associations between polygenic risk for accelerated intrinsic epigenetic ageing, SES, and the Levine clock, indicating that genetic risk and social disadvantage may contribute additively to faster biological aging.

Estimating genetic nurture with summary statistics of multigenerational genome-wide association studies.

Marginal effect estimates in genome-wide association studies (GWAS) are mixtures of direct and indirect genetic effects. Existing methods to dissect these effects require family-based, individual-level genetic, and phenotypic data with large samples, which is difficult to obtain in practice. Here, we propose a statistical framework to estimate direct and indirect genetic effects using summary statistics from GWAS conducted on own and offspring phenotypes. Applied to birth weight, our method showed nearly identical results with those obtained using individual-level data. We also decomposed direct and indirect genetic effects of educational attainment (EA), which showed distinct patterns of genetic correlations with 45 complex traits. The known genetic correlations between EA and higher height, lower body mass index, less-active smoking behavior, and better health outcomes were mostly explained by the indirect genetic component of EA. In contrast, the consistently identified genetic correlation of autism spectrum disorder (ASD) with higher EA resides in the direct genetic component. A polygenic transmission disequilibrium test showed a significant overtransmission of the direct component of EA from healthy parents to ASD probands. Taken together, we demonstrate that traditional GWAS approaches, in conjunction with offspring phenotypic data collection in existing cohorts, could greatly benefit studies on genetic nurture and shed important light on the interpretation of genetic associations for human complex traits.

Metabolites Associated with Early Cognitive Changes Implicated in Alzheimer's Disease.

BACKGROUND: Understanding metabolic mechanisms associated with cognitive changes preceding an Alzheimer's disease (AD) diagnosis could advance our understanding of AD progression and inform preventive methods. OBJECTIVE: We investigated the metabolomics of the early changes in executive function and delayed recall, the earliest aspects of cognitive function to change in the course of AD development, in order to better understand mechanisms that could contribute to early stages and progression of this disease. METHODS: This investigation used longitudinal plasma samples from the Wisconsin Registry for Alzheimer's Prevention (WRAP), a cohort of participants who were dementia free at enrollment and enriched with a parental history of AD. Metabolomic profiles were quantified for 2,324 fasting plasma samples among 1,200 participants, each with up to three study visits, which occurred every two years. Metabolites were individually tested for association with executive function and delayed recall trajectories across age. RESULTS: Of 1,097 metabolites tested, levels of seven were associated with executive function trajectories, including an amino acid cysteine S-sulfate and three fatty acids, including erucate (22 : 1n9), while none were associated with delayed recall trajectories. Replication was attempted for four of these metabolites that were present in the Vietnam Era Twin Study of Aging (VETSA). Although none reached statistical significance, three of these associations showed consistent effectdirections. CONCLUSION: Our results suggest potential metabolomic mechanisms that could contribute to the earliest signs of cognitive decline. In particular, fatty acids may be associated with cognition in a manner that is more complex than previously suspected.

Genome-wide Association Study of Maximum Habitual Alcohol Intake in >140,000 U.S. European and African American Veterans Yields Novel Risk Loci.

BACKGROUND: Habitual alcohol use can be an indicator of alcohol dependence, which is associated with a wide range of serious health problems. METHODS: We completed a genome-wide association study in 126,936 European American and 17,029 African American subjects in the Veterans Affairs Million Veteran Program for a quantitative phenotype based on maximum habitual alcohol consumption. RESULTS: ADH1B, on chromosome 4, was the lead locus for both populations: for the European American sample, rs1229984 (p = 4.9 × 10-47); for African American, rs2066702 (p = 2.3 × 10-12). In the European American sample, we identified three additional genome-wide-significant maximum habitual alcohol consumption loci: on chromosome 17, rs77804065 (p = 1.5 × 10-12), at CRHR1 (corticotropin-releasing hormone receptor 1); the protein product of this gene is involved in stress and immune responses; and on chromosomes 8 and 10. European American and African American samples were then meta-analyzed; the associated region at CRHR1 increased in significance to 1.02 × 10-13, and we identified two additional genome-wide significant loci, FGF14 (p = 9.86 × 10-9) (chromosome 13) and a locus on chromosome 11. Besides ADH1B, none of the five loci have prior genome-wide significant support. Post-genome-wide association study analysis identified genetic correlation to other alcohol-related traits, smoking-related traits, and many others. Replications were observed in UK Biobank data. Genetic correlation between maximum habitual alcohol consumption and alcohol dependence was 0.87 (p = 4.78 × 10-9). Enrichment for cell types included dopaminergic and gamma-aminobutyric acidergic neurons in midbrain, and pancreatic delta cells. CONCLUSIONS: The present study supports five novel alcohol-use risk loci, with particularly strong statistical support for CRHR1. Additionally, we provide novel insight regarding the biology of harmful alcohol use.

Mutations in Chromatin Modifier and Ephrin Signaling Genes in Vein of Galen Malformation.

Normal vascular development includes the formation and specification of arteries, veins, and intervening capillaries. Vein of Galen malformations (VOGMs) are among the most common and severe neonatal brain arterio-venous malformations, shunting arterial blood into the brain's deep venous system through aberrant direct connections. Exome sequencing of 55 VOGM probands, including 52 parent-offspring trios, revealed enrichment of rare damaging de novo mutations in chromatin modifier genes that play essential roles in brain and vascular development. Other VOGM probands harbored rare inherited damaging mutations in Ephrin signaling genes, including a genome-wide significant mutation burden in EPHB4. Inherited mutations showed incomplete penetrance and variable expressivity, with mutation carriers often exhibiting cutaneous vascular abnormalities, suggesting a two-hit mechanism. The identified mutations collectively account for ∼30% of studied VOGM cases. These findings provide insight into disease biology and may have clinical implications for risk assessment.

A Genome-Wide Association Study to Identify Single-Nucleotide Polymorphisms for Acute Kidney Injury.

RATIONALE: Acute kidney injury is a common and severe complication of critical illness and cardiac surgery. Despite significant attempts at developing treatments, therapeutic advances to attenuate acute kidney injury and expedite recovery have largely failed. OBJECTIVES: Identifying genetic loci associated with increased risk of acute kidney injury may reveal novel pathways for therapeutic development. METHODS: We conducted an exploratory genome-wide association study to identify single-nucleotide polymorphisms associated with genetic susceptibility to in-hospital acute kidney injury. MEASUREMENTS AND MAIN RESULTS: We genotyped 609,508 single-nucleotide polymorphisms and performed genotype imputation in 760 acute kidney injury cases and 669 controls. We then evaluated polymorphisms that showed the strongest association with acute kidney injury in a replication patient population containing 206 cases with 1,406 controls. We observed an association between acute kidney injury and four single-nucleotide polymorphisms at two independent loci on metaanalysis of discovery and replication populations. These include rs62341639 (metaanalysis P = 2.48 × 10-7; odds ratio [OR], 0.64; 95% confidence interval [CI], 0.55-0.76) and rs62341657 (P = 3.26 × 10-7; OR, 0.65; 95% CI, 0.55-0.76) on chromosome 4 near APOL1-regulator IRF2, and rs9617814 (metaanalysis P = 3.81 × 10-6; OR, 0.70; 95% CI, 0.60-0.81) and rs10854554 (P = 6.53 × 10-7; OR, 0.67; 95% CI, 0.57-0.79) on chromosome 22 near acute kidney injury-related gene TBX1. CONCLUSIONS: Our findings reveal two genetic loci that are associated with acute kidney injury. Additional studies should be conducted to functionally evaluate these loci and to identify other common genetic variants contributing to acute kidney injury.

GenoWAP: GWAS signal prioritization through integrated analysis of genomic functional annotation.

MOTIVATION: Genome-wide association study (GWAS) has been a great success in the past decade. However, significant challenges still remain in both identifying new risk loci and interpreting results. Bonferroni-corrected significance level is known to be conservative, leading to insufficient statistical power when the effect size is moderate at risk locus. Complex structure of linkage disequilibrium also makes it challenging to separate causal variants from nonfunctional ones in large haplotype blocks. Under such circumstances, a computational approach that may increase signal replication rate and identify potential functional sites among correlated markers is urgently needed. RESULTS: We describe GenoWAP, a GWAS signal prioritization method that integrates genomic functional annotation and GWAS test statistics. The effectiveness of GenoWAP is demonstrated through its applications to Crohn's disease and schizophrenia using the largest studies available, where highly ranked loci show substantially stronger signals in the whole dataset after prioritization based on a subset of samples. At the single nucleotide polymorphism (SNP) level, top ranked SNPs after prioritization have both higher replication rates and consistently stronger enrichment of eQTLs. Within each risk locus, GenoWAP may be able to distinguish functional sites from groups of correlated SNPs. AVAILABILITY AND IMPLEMENTATION: GenoWAP is freely available on the web at http://genocanyon.med.yale.edu/GenoWAP.