Yogasudha Veturi

Pennsylvania State University | Penn State · Department of Biobehavioral Health

The complex biological mechanisms underlying human brain aging remain incompletely understood. This study investigated the genetic architecture of three brain age gaps (BAG) derived from gray matter volume (GM-BAG), white matter microstructure (WM-BAG), and functional connectivity (FC-BAG). We identified sixteen genomic loci that reached genome-wid...

Normal and pathologic neurobiological processes influence brain morphology in coordinated ways that give rise to patterns of structural covariance (PSC) across brain regions and individuals during brain aging and diseases. The genetic underpinnings of these patterns remain largely unknown. We apply a stochastic multivariate factorization method to...

The complex biological mechanisms underlying human brain aging remain incompletely understood. To investigate this, we utilized multimodal magnetic resonance imaging and artificial intelligence (AI) to examine the genetic heterogeneity of the brain age gap (BAG) derived from gray matter volume (GM-BAG), white matter tract (WM-BAG), and functional c...

Leveraging linkage disequilibrium (LD) patterns as representative of population substructure enables the discovery of additive association signals in genome-wide association studies (GWASs). Standard GWASs are well-powered to interrogate additive models; however, new approaches are required for invesigating other modes of inheritance such as domina...

This PSB 2023 session discusses challenges in clinical implication and application of risk prediction models, which includes but is not limited to: implementation of risk models, responsible use of polygenic risk scores (PGS), and other risk prediction strategies. We focus on the development and use of new, scalable methods for harmonizing and refi...

Background Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results To expand our understa...

Meta-analysis is pervasively used to combine multiple genome-wide association studies (GWASs). Fine-mapping of meta-analysis studies is typically performed as in a single-cohort study. Here, we first demonstrate that heterogeneity (e.g., of sample size, phenotyping, imputation) hurts calibration of meta-analysis fine-mapping. We propose a summary s...

Leveraging linkage disequilibrium (LD) patterns as representative of population substructure enables the discovery of additive association signals in genome-wide association studies (GWAS). Standard GWAS are well-powered to interrogate additive models; however, new approaches are required to investigate other modes of inheritance such as dominance...

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40–50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes¹. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 inde...

Biobanks facilitate genome-wide association studies (GWASs), which have mapped genomic loci across a range of human diseases and traits. However, most biobanks are primarily composed of individuals of European ancestry. We introduce the Global Biobank Meta-analysis Initiative (GBMI)—a collaborative network of 23 biobanks from 4 continents represent...

A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We fir...

Normal and pathologic neurobiological processes influence brain morphology in coordinated ways that give rise to patterns of structural covariance (PSC) across brain regions and individuals during brain aging and diseases. The genetic underpinnings of these patterns remain largely unknown. We apply a stochastic multivariate factorization method to...

Clinical and epidemiological studies have shown that circulatory system diseases and nervous system disorders often co-occur in patients. However, genetic susceptibility factors shared between these disease categories remain largely unknown. Here, we characterized pleiotropy across 107 circulatory system and 40 nervous system traits using an ensemb...

Normal and pathologic neurobiological processes influence brain morphology in coordinated ways that give rise to structural covariance patterns across brain regions and individuals. We present a mega-analysis of structural covariance with magnetic resonance imaging of 50,699 healthy and diseased individuals (12 studies, 130 sites, and 12 countries)...

Importance: Late-life depression (LLD) is characterized by considerable heterogeneity in clinical manifestation. Unraveling such heterogeneity might aid in elucidating etiological mechanisms and support precision and individualized medicine. Objective: To cross-sectionally and longitudinally delineate disease-related heterogeneity in LLD associa...

BACKGROUND: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. RESULTS: To expand our underst...

Genetic variants within nearly 1,000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. To expand our understanding of the underl...

Increased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use¹. Despite advances in prevention and treatment, in particular through reducing low-density lipoprotein cholesterol levels², heart disease remains the leading cause of death worldwi...

A major challenge of genome-wide association studies (GWAS) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We firs...

Genome‐wide genotyping and analysis approaches offer the opportunity to examine patterns of variation across a large number of genomic positions for association with occurrence of disease or the distribution of traits of interest. Genome‐wide association studies (GWAS) efforts require rigorous planning and careful study design at their outset. The...

Understanding genetic factors of complex traits across ancestry groups holds a key to improve the overall health care quality for diverse populations in the United States. In recent years, multiple electronic health record-linked (EHR-linked) biobanks have recruited participants of diverse ancestry backgrounds; these biobanks make it possible to ob...

Late-life depression (LLD) is characterized by considerable heterogeneity in clinical manifestation. Unraveling such heterogeneity would aid in elucidating etiological mechanisms and pave the road to precision and individualized medicine. We sought to delineate, cross-sectionally and longitudinally, disease-related heterogeneity in LLD linked to ne...

Plasma lipids are known heritable risk factors for cardiovascular disease, but increasing evidence also supports shared genetics with diseases of other organ systems. We devised a comprehensive three-phase framework to identify new lipid-associated genes and study the relationships among lipids, genotypes, gene expression and hundreds of complex hu...

As a type of relatively new methodology, the transcriptome-wide association study (TWAS) has gained interest due to capacity for gene-level association testing. However, the development of TWAS has outpaced statistical evaluation of TWAS gene prioritization performance. Current TWAS methods vary in underlying biological assumptions about tissue spe...

As a type of relatively new methodology, the transcriptome-wide association study (TWAS) has gained interest due to capacity for gene-level association testing. However, the development of TWAS has outpaced statistical evaluation of TWAS gene prioritization performance. Current TWAS methods vary in underlying biological assumptions about tissue spe...

Abstract Characterizing how variation at the level of individual nucleotides contributes to traits and diseases has been an area of growing interest since the completion of sequencing the first human genome. Our understanding of how a single nucleotide polymorphism (SNP) leads to a pathogenic phenotype on a genome-wide scale is a fruitful endeavor...

In humans, most genome-wide association studies have been conducted using data from Caucasians and many of the reported findings have not replicated in other populations. This lack of replication may be due to statistical issues (small sample sizes or confounding) or perhaps more fundamentally to differences in the genetic architecture of traits be...

Transcriptome-wide association studies (TWAS) have recently gained great attention due to their ability to prioritize complex trait-associated genes and promote potential therapeutics development for complex human diseases. TWAS integrates genotypic data with expression quantitative trait loci (eQTLs) to predict genetically regulated gene expressio...

The link between cardiovascular diseases and neurological disorders has been widely observed in the aging population. Disease prevention and treatment rely on understanding the potential genetic nexus of multiple diseases in these categories. In this study, we were interested in detecting pleiotropy, or the phenomenon in which a genetic variant inf...

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

The location and type of adipose tissue is an important factor in metabolic syndrome. A database of picture archiving and communication system (PACS) derived abdominal computerized tomography (CT) images from a large health care provider, Geisinger, was used for large-scale research of the relationship of volume of subcutaneous adipose tissue (SAT)...

In humans, most genome-wide association studies have been conducted using data from Caucasians and many of the reported findings have not replicated in other populations. This lack of replication may be due to statistical issues (small sample size, confounding) or perhaps more fundamentally to differences in the genetic architecture of traits betwe...

Background Machine learning methods have gained popularity and practicality in identifying linear and non-linear effects of variants associated with complex disease/traits. Detection of epistatic interactions still remains a challenge due to the large number of features and relatively small sample size as input, thus leading to the so-called “short...

Background Machine learning methods have gained popularity and practicality in identifying linear and non-linear effects of variants associated with complex disease/traits. Detection of epistatic interactions still remains a challenge due to the large number of features and relatively small sample size as input, thus leading to the so-called “short...

The DrugBank database consists of ~800 genes that are well characterized drug targets. This list of genes is a useful resource for association testing. For example, loss of function (LOF) genetic variation has the potential to mimic the effect of drugs, and high impact variation in these genes can impact downstream traits. Identifying novel associa...

Genome-wide association studies (GWAS) have been successful in facilitating the understanding of genetic architecture behind human diseases, but this approach faces many challenges. To identify disease-related loci with modest to weak effect size, GWAS requires very large sample sizes, which can be computational burdensome. In addition, the interpr...

Transcriptome-wide association studies (TWAS) have recently been employed as an approach that can draw upon the advantages of genome-wide association studies (GWAS) and gene expression studies to identify genes associated with complex traits. Unlike standard GWAS, summary level data suffices for TWAS and offers improved statistical power. Two popul...

Whole-genome multi-omic profiles hold valuable information for the analysis and prediction of disease risk and progression. However, integrating high-dimensional multi-layer omic data into risk assessment models is statistically and computationally challenging. We describe a statistical framework (BGAM=Bayesian Generalized Additive Model) and prese...

Naturally and artificially selected populations usually exhibit some degree of stratification. In Genome-Wide Association Studies and in Whole-Genome Regressions (WGR) analyses, population stratification has been either ignored or dealt with as a potential confounder. However, systematic differences in allele frequency and in patterns of linkage di...

Lifestyle and genetic factors play a large role in the development of Type 2 Diabetes (T2D). Despite the important role of genetic factors, genetic information is not incorporated into the clinical assessment of T2D risk. We assessed and compared Whole Genome Regression methods to predict the T2D status of 5,245 subjects from the Framingham Heart S...

Figure S3 Difference in prediction accuracy by scenario and data used.

Figure S4 Differences between GBLUP methods in the analysis of human height.

Table S2 Genomic heritability estimates obtained with the GBLUP method in the LOW‐MAF scenario by: genetic architecture simulated. data used and Monte Carlo replicate.

Table S3 Average (SD, both across Monte Carlo replicates) correlation between simulated phenotype and predictions in Training data sets by method, simulation scenario and data used for the analysis.

Table S5 Correlation and R 2 between human height and genomic predictions in testing data sets by method and testing set.

Figure S2 R 2 statistic in training data sets.

Figure S1 Prior distributions commonly used in Bayesian regression models.

Table S1 Genomic heritability estimates obtained with the GBLUP method in the RAND scenario by: genetic architecture simulated, data used and Monte Carlo replicate.

Table S4 Average (SD, both across 30 replicates) R 2 in validation data sets by simulation scenario, data used for analysis and estimation method.

Genome-wide association studies (GWAS) have detected large numbers of variants associated with complex human traits and diseases. However, the proportion of variance explained by GWAS-significant single nucleotide polymorphisms has been usually small. This brought interest in the use of whole-genome regression (WGR) methods. However, there has been...

ABSTRACT The mixed linear model (MLM) is an advanced statistical technique applicable to many fields of science. The multivariate MLM can be used to model longitudinal data, such as repeated ratings of disease resistance taken across time. In this study, using an example data set from a multi-environment trial of northern leaf blight disease on 290...

Package inserts of Food and Drug Administration (FDA) approved prescription drugs, including chemotherapy drugs, must follow a specific format imposed by the FDA. These inserts are created by unrelated pharmaceutical companies and as a result tend to be very different in the way the required information is reported. Chemical and pharmacokinetic pro...

The response to environmental variables such as day length and temperature has limited the adaptation and use of ‘exotic’ sources of maize for N. American production. The USDA-NIFA Maize ATLAS (Adaptation Through Latitudinal Artificial Selection) project aims to: 1) phenotypically, genetically, and ecologically characterize genomic loci limiting th...

Association or linkage disequilibrium (LD) mapping allows for the identification of quantitative trait loci based on correlations between sequence and trait variation. Genetic structure refers to different levels of genetic relatedness between individuals in a population. Factors such as recombination, independent assortment, migration, mutation, a...