Decomposing heritability and genetic covariance by direct and indirect effect paths.

Estimation of heritability and genetic covariance is crucial for quantifying and understanding complex trait genetic architecture and is employed in almost all recent genome-wide association studies (GWAS). However, many existing approaches for heritability estimation and almost all methods for estimating genetic correlation ignore the presence of indirect genetic effects, i.e., genotype-phenotype associations confounded by the parental genome and family environment, and may thus lead to incorrect interpretation especially for human sociobehavioral phenotypes. In this work, we introduce a statistical framework to decompose heritability and genetic covariance into multiple components representing direct and indirect effect paths. Applied to five traits in UK Biobank, we found substantial involvement of indirect genetic components in shared genetic architecture across traits. These results demonstrate the effectiveness of our approach and highlight the importance of accounting for indirect effects in variance component analysis of complex traits.

A quantile integral linear model to quantify genetic effects on phenotypic variability.

Detecting genetic variants associated with the variance of complex traits, that is, variance quantitative trait loci (vQTLs), can provide crucial insights into the interplay between genes and environments and how they jointly shape human phenotypes in the population. We propose a quantile integral linear model (QUAIL) to estimate genetic effects on trait variability. Through extensive simulations and analyses of real data, we demonstrate that QUAIL provides computationally efficient and statistically powerful vQTL mapping that is robust to non-Gaussian phenotypes and confounding effects on phenotypic variability. Applied to UK Biobank (n = 375,791), QUAIL identified 11 vQTLs for body mass index (BMI) that have not been previously reported. Top vQTL findings showed substantial enrichment for interactions with physical activities and sedentary behavior. Furthermore, variance polygenic scores (vPGSs) based on QUAIL effect estimates showed superior predictive performance on both population-level and within-individual BMI variability compared to existing approaches. Overall, QUAIL is a unified framework to quantify genetic effects on the phenotypic variability at both single-variant and vPGS levels. It addresses critical limitations in existing approaches and may have broad applications in future gene-environment interaction studies.

Neuropathology-based APOE genetic risk score better quantifies Alzheimer's risk.

INTRODUCTION: Apolipoprotein E (APOE) ε4-carrier status or ε4 allele count are included in analyses to account for the APOE genetic effect on Alzheimer's disease (AD); however, this does not account for protective effects of APOE ε2 or heterogeneous effect of ε2, ε3, and ε4 haplotypes. METHODS: We leveraged results from an autopsy-confirmed AD study to generate a weighted risk score for APOE (APOE-npscore). We regressed cerebrospinal fluid (CSF) amyloid and tau biomarkers on APOE variables from the Wisconsin Registry for Alzheimer's Prevention (WRAP), Wisconsin Alzheimer's Disease Research Center (WADRC), and Alzheimer's Disease Neuroimaging Initiative (ADNI). RESULTS: The APOE-npscore explained more variance and provided a better model fit for all three CSF measures than APOE ε4-carrier status and ε4 allele count. These findings were replicated in ADNI and observed in subsets of cognitively unimpaired (CU) participants. DISCUSSION: The APOE-npscore reflects the genetic effect on neuropathology and provides an improved method to account for APOE in AD-related analyses.

Conformal Prediction Based on K-Nearest Neighbors for Discrimination of Ginsengs by a Home-Made Electronic Nose.

An estimate on the reliability of prediction in the applications of electronic nose is essential, which has not been paid enough attention. An algorithm framework called conformal prediction is introduced in this work for discriminating different kinds of ginsengs with a home-made electronic nose instrument. Nonconformity measure based on k-nearest neighbors (KNN) is implemented separately as underlying algorithm of conformal prediction. In offline mode, the conformal predictor achieves a classification rate of 84.44% based on 1NN and 80.63% based on 3NN, which is better than that of simple KNN. In addition, it provides an estimate of reliability for each prediction. In online mode, the validity of predictions is guaranteed, which means that the error rate of region predictions never exceeds the significance level set by a user. The potential of this framework for detecting borderline examples and outliers in the application of E-nose is also investigated. The result shows that conformal prediction is a promising framework for the application of electronic nose to make predictions with reliability and validity.

Valid Probabilistic Predictions for Ginseng with Venn Machines Using Electronic Nose.

In the application of electronic noses (E-noses), probabilistic prediction is a good way to estimate how confident we are about our prediction. In this work, a homemade E-nose system embedded with 16 metal-oxide semi-conductive gas sensors was used to discriminate nine kinds of ginsengs of different species or production places. A flexible machine learning framework, Venn machine (VM) was introduced to make probabilistic predictions for each prediction. Three Venn predictors were developed based on three classical probabilistic prediction methods (Platt's method, Softmax regression and Naive Bayes). Three Venn predictors and three classical probabilistic prediction methods were compared in aspect of classification rate and especially the validity of estimated probability. A best classification rate of 88.57% was achieved with Platt's method in offline mode, and the classification rate of VM-SVM (Venn machine based on Support Vector Machine) was 86.35%, just 2.22% lower. The validity of Venn predictors performed better than that of corresponding classical probabilistic prediction methods. The validity of VM-SVM was superior to the other methods. The results demonstrated that Venn machine is a flexible tool to make precise and valid probabilistic prediction in the application of E-nose, and VM-SVM achieved the best performance for the probabilistic prediction of ginseng samples.

Optimal Sensor Selection for Classifying a Set of Ginsengs Using Metal-Oxide Sensors.

The sensor selection problem was investigated for the application of classification of a set of ginsengs using a metal-oxide sensor-based homemade electronic nose with linear discriminant analysis. Samples (315) were measured for nine kinds of ginsengs using 12 sensors. We investigated the classification performances of combinations of 12 sensors for the overall discrimination of combinations of nine ginsengs. The minimum numbers of sensors for discriminating each sample set to obtain an optimal classification performance were defined. The relation of the minimum numbers of sensors with number of samples in the sample set was revealed. The results showed that as the number of samples increased, the average minimum number of sensors increased, while the increment decreased gradually and the average optimal classification rate decreased gradually. Moreover, a new approach of sensor selection was proposed to estimate and compare the effective information capacity of each sensor.

Statistical methods for gene-environment interaction analysis.

Most human complex phenotypes result from multiple genetic and environmental factors and their interactions. Understanding the mechanisms by which genetic and environmental factors interact offers valuable insights into the genetic architecture of complex traits and holds great potential for advancing precision medicine. The emergence of large population biobanks has led to the development of numerous statistical methods aiming at identifying gene-environment interactions (G × E). In this review, we present state-of-the-art statistical methodologies for G × E analysis. We will survey a spectrum of approaches for single-variant G × E mapping, followed by various techniques for polygenic G × E analysis. We conclude this review with a discussion on the future directions and challenges in G × E research.

Controlling for polygenic genetic confounding in epidemiologic association studies.

Epidemiologic associations estimated from observational data are often confounded by genetics due to pervasive pleiotropy among complex traits. Many studies either neglect genetic confounding altogether or rely on adjusting for polygenic scores (PGS) in regression analysis. In this study, we unveil that the commonly employed PGS approach is inadequate for removing genetic confounding due to measurement error and model misspecification. To tackle this challenge, we introduce PENGUIN, a principled framework for polygenic genetic confounding control based on variance component estimation. In addition, we present extensions of this approach that can estimate genetically-unconfounded associations using GWAS summary statistics alone as input and between multiple generations of study samples. Through simulations, we demonstrate superior statistical properties of PENGUIN compared to the existing approaches. Applying our method to multiple population cohorts, we reveal and remove substantial genetic confounding in the associations of educational attainment with various complex traits and between parental and offspring education. Our results show that PENGUIN is an effective solution for genetic confounding control in observational data analysis with broad applications in future epidemiologic association studies.

Quantifying portable genetic effects and improving cross-ancestry genetic prediction with GWAS summary statistics.

Polygenic risk scores (PRS) calculated from genome-wide association studies (GWAS) of Europeans are known to have substantially reduced predictive accuracy in non-European populations, limiting their clinical utility and raising concerns about health disparities across ancestral populations. Here, we introduce a statistical framework named X-Wing to improve predictive performance in ancestrally diverse populations. X-Wing quantifies local genetic correlations for complex traits between populations, employs an annotation-dependent estimation procedure to amplify correlated genetic effects between populations, and combines multiple population-specific PRS into a unified score with GWAS summary statistics alone as input. Through extensive benchmarking, we demonstrate that X-Wing pinpoints portable genetic effects and substantially improves PRS performance in non-European populations, showing 14.1%-119.1% relative gain in predictive R2 compared to state-of-the-art methods based on GWAS summary statistics. Overall, X-Wing addresses critical limitations in existing approaches and may have broad applications in cross-population polygenic risk prediction.

Neurogenetic mechanisms of risk for ADHD: Examining associations of polygenic scores and brain volumes in a population cohort.

BACKGROUND: ADHD polygenic scores (PGSs) have been previously shown to predict ADHD outcomes in several studies. However, ADHD PGSs are typically correlated with ADHD but not necessarily reflective of causal mechanisms. More research is needed to elucidate the neurobiological mechanisms underlying ADHD. We leveraged functional annotation information into an ADHD PGS to (1) improve the prediction performance over a non-annotated ADHD PGS and (2) test whether volumetric variation in brain regions putatively associated with ADHD mediate the association between PGSs and ADHD outcomes. METHODS: Data were from the Philadelphia Neurodevelopmental Cohort (N = 555). Multiple mediation models were tested to examine the indirect effects of two ADHD PGSs-one using a traditional computation involving clumping and thresholding and another using a functionally annotated approach (i.e., AnnoPred)-on ADHD inattention (IA) and hyperactivity-impulsivity (HI) symptoms, via gray matter volumes in the cingulate gyrus, angular gyrus, caudate, dorsolateral prefrontal cortex (DLPFC), and inferior temporal lobe. RESULTS: A direct effect was detected between the AnnoPred ADHD PGS and IA symptoms in adolescents. No indirect effects via brain volumes were detected for either IA or HI symptoms. However, both ADHD PGSs were negatively associated with the DLPFC. CONCLUSIONS: The AnnoPred ADHD PGS was a more developmentally specific predictor of adolescent IA symptoms compared to the traditional ADHD PGS. However, brain volumes did not mediate the effects of either a traditional or AnnoPred ADHD PGS on ADHD symptoms, suggesting that we may still be underpowered in clarifying brain-based biomarkers for ADHD using genetic measures.

Pervasive biases in proxy GWAS based on parental history of Alzheimer's disease.

Almost every recent Alzheimer's disease (AD) genome-wide association study (GWAS) has performed meta-analysis to combine studies with clinical diagnosis of AD with studies that use proxy phenotypes based on parental disease history. Here, we report major limitations in current GWAS-by-proxy (GWAX) practices due to uncorrected survival bias and non-random participation of parental illness survey, which cause substantial discrepancies between AD GWAS and GWAX results. We demonstrate that current AD GWAX provide highly misleading genetic correlations between AD risk and higher education which subsequently affects a variety of genetic epidemiologic applications involving AD and cognition. Our study sheds important light on the design and analysis of mid-aged biobank cohorts and underscores the need for caution when interpreting genetic association results based on proxy-reported parental disease history.

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.

The impact of late-career job loss and genetic risk on body mass index: Evidence from variance polygenic scores.

Unemployment shocks from the COVID-19 pandemic have reignited concerns over the long-term effects of job loss on population health. Past research has highlighted the corrosive effects of unemployment on health and health behaviors. This study examines whether the effects of job loss on changes in body mass index (BMI) are moderated by genetic predisposition using data from the U.S. Health and Retirement Study (HRS). To improve detection of gene-by-environment (G × E) interplay, we interacted layoffs from business closures-a plausibly exogenous environmental exposure-with whole-genome polygenic scores (PGSs) that capture genetic contributions to both the population mean (mPGS) and variance (vPGS) of BMI. Results show evidence of genetic moderation using a vPGS (as opposed to an mPGS) and indicate genome-wide summary measures of phenotypic plasticity may further our understanding of how environmental stimuli modify the distribution of complex traits in a population.