Imaging Genetics Data Research Articles

Groupwise envelope models for imaging genetic analysis.

Motivated by searching for associations between genetic variants and brain imaging phenotypes, the aim of this article is to develop a groupwise envelope model for multivariate linear regression in order to establish the association between both multivariate responses and covariates. The groupwise envelope model allows for both distinct regression coefficients and distinct error structures for different groups. Statistically, the proposed envelope model can dramatically improve efficiency of tests and of estimation. Theoretical properties of the proposed model are established. Numerical experiments as well as the analysis of an imaging genetic data set obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study show the effectiveness of the model in efficient estimation. Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database.

Longitudinal Genotype-Phenotype Association Study via Temporal Structure Auto-Learning Predictive Model.

With rapid progress in high-throughput genotyping and neuroimaging, imaging genetics has gained significant attention in the research of complex brain disorders, such as Alzheimer's Disease (AD). The genotype-phenotype association study using imaging genetic data has the potential to reveal genetic basis and biological mechanism of brain structure and function. AD is a progressive neurodegenerative disease, thus, it is crucial to look into the relations between SNPs and longitudinal variations of neuroimaging phenotypes. Although some machine learning models were newly presented to capture the longitudinal patterns in genotype-phenotype association study, most of them required fixed longitudinal structures of prediction tasks and could not automatically learn the interrelations among longitudinal prediction tasks. To address this challenge, we proposed a novel temporal structure auto-learning model to automatically uncover longitudinal genotype-phenotype interrelations and utilized such interrelated structures to enhance phenotype prediction in the meantime. We conducted longitudinal phenotype prediction experiments on the ADNI cohort including 3,123 SNPs and 2 types of biomarkers, VBM and FreeSurfer. Empirical results demonstrated advantages of our proposed model over the counterparts. Moreover, available literature was identified for our top selected SNPs, which demonstrated the rationality of our prediction results. An executable program is available online at https://github.com/littleq1991/sparse_lowRank_regression.

M63 - Genome Wide Association Results of Alcoholic Use Disorder Patients And Healthy Controls

Background Recent genome wide association studies (GWAS) of alcoholic use disorder (AUD) have estimated a 40-60% variance explained by common genetic variants. Since GWAS require large sample sizes this study aims at combining genetics and imaging data to help finding genetics risk variants in smaller datasets (referred to as imaging genetics data). In this presentation we will focus on the genetic results of this study Methods We had genotypic data of 115 cases of AUD according to DSM-IV-TR and 286 healthy controls. We used Ricopili pipeline for quality control (QC), principal component analysis (PCA), imputation, association analysis and polygenic risk scoring. Standard thresholds during QC were applied: call rate for individuals 98%, call rate for SNPs 98%, missing differences between cases and controls 2%, Hardy Weinberg Equilibrium for controls 10e-06, HWE for case 10e-10. We also checked for sex inconsistencies between reported sex and empirical sex as well as for related individuals between all the individuals by using identity by descent on a set of LD-pruned SNPs. After removing the related and overlapping individuals, PCA results were checked for hidden population stratification. Pre-phasing was done using Shapeit and imputation using Impute2 (using 1000 Genomes phase 1 as reference). We clumped GWAS summary statistics from the biggest currently available AUD dataset (n=16,087) and scored the individuals of our study. We also inspected for genetic correlation between Schizophrenia by using the largest available data sets from the Psychiatric Genomic Consortium (PGC). Results All cases passed QC but four controls were excluded due to call rate. Out of 603,132 SNPs, 42% (253,361) were excluded, most of which were invariant (39%). PCA revealed slight population stratification without strong outliers; overlap testing could reveal one related and one completely overlapping case, of which one each was excluded from downstream analysis. After imputation 8,696,851 SNPs, 115 cases and 280 controls were chosen for the analysis. As expected, we did not find any genome wide significant SNPs. The QQ plots showed only slight inflation from expectation (lambda=1.054). Polygenic risk score with four alcoholism phenotypes (two Discovery sample for alcohol dependent and ordinal trait and two SAGE sample with alcohol dependent and ordinal trait) (Gelernter J, et al, 2014) could not show significant separation of cases and controls in our study for any of the p-value thresholds. We also found no significant correlation with schizophrenia as the training dataset. Discussion QC, imputation of this study was straightforward and as expected could not identify new genome wide significant SNPs. The genetic data is now ready to use to understand more about genetic aetiology of AUD using imaging genetics. Polygenic risk scoring with the biggest data available for AUD GWAS showed no signal, which might be due to low power of the training data (Gelernter J, et al, 2014). Newer and much more powerful PGC results will soon give more insight. As expected this study also showed no genetic association with schizophrenia.

Genome-wide association analysis of secondary imaging phenotypes from the Alzheimer's disease neuroimaging initiative study

The aim of this paper is to systematically evaluate a biased sampling issue associated with genome-wide association analysis (GWAS) of imaging phenotypes for most imaging genetic studies, including the Alzheimer's Disease Neuroimaging Initiative (ADNI). Specifically, the original sampling scheme of these imaging genetic studies is primarily the retrospective case-control design, whereas most existing statistical analyses of these studies ignore such sampling scheme by directly correlating imaging phenotypes (called the secondary traits) with genotype. Although it has been well documented in genetic epidemiology that ignoring the case-control sampling scheme can produce highly biased estimates, and subsequently lead to misleading results and suspicious associations, such findings are not well documented in imaging genetics. We use extensive simulations and a large-scale imaging genetic data analysis of the Alzheimer's Disease Neuroimaging Initiative (ADNI) data to evaluate the effects of the case-control sampling scheme on GWAS results based on some standard statistical methods, such as linear regression methods, while comparing it with several advanced statistical methods that appropriately adjust for the case-control sampling scheme.

Fine-mapping the effects of Alzheimer's disease risk loci on brain morphology

The neural substrate of genetic risk variants for Alzheimer's disease (AD) remains unknown. We studied their effect on healthy brain morphology to provide insight into disease etiology in the preclinical phase. We included 4071 nondemented, elderly participants of the population-based Rotterdam Study who underwent brain magnetic resonance imaging and genotyping. We performed voxel-based morphometry (VBM) on all gray-matter voxels for 19 previously identified, common AD risk variants. Whole-brain expression data from the Allen Human Brain Atlas was used to examine spatial overlap between VBM association results and expression of genes in AD risk loci regions. Brain regions most significantly associated with AD risk variants were the left postcentral gyrus with ABCA7 (rs4147929, p = 4.45 × 10−6), right superior frontal gyrus by ZCWPW1 (rs1476679, p = 5.12 × 10−6), and right postcentral gyrus by APOE (p = 6.91 × 10−6). Although no individual voxel passed multiple-testing correction, we found significant spatial overlap between the effects of AD risk loci on VBM and the expression of genes (MEF2C, CLU, and SLC24A4) in the Allen Brain Atlas. Results are available online on www.imagene.nl/ADSNPs/. In this single largest imaging genetics data set worldwide, we found that AD risk loci affect cortical gray matter in several brain regions known to be involved in AD, as well as regions that have not been implicated before.

Two-dimensional enrichment analysis for mining high-level imaging genetic associations

Enrichment analysis has been widely applied in the genome-wide association studies, where gene sets corresponding to biological pathways are examined for significant associations with a phenotype to help increase statistical power and improve biological interpretation. In this work, we expand the scope of enrichment analysis into brain imaging genetics, an emerging field that studies how genetic variation influences brain structure and function measured by neuroimaging quantitative traits (QT). Given the high dimensionality of both imaging and genetic data, we propose to study Imaging Genetic Enrichment Analysis (IGEA), a new enrichment analysis paradigm that jointly considers meaningful gene sets (GS) and brain circuits (BC) and examines whether any given GS–BC pair is enriched in a list of gene–QT findings. Using gene expression data from Allen Human Brain Atlas and imaging genetics data from Alzheimer’s Disease Neuroimaging Initiative as test beds, we present an IGEA framework and conduct a proof-of-concept study. This empirical study identifies 25 significant high-level two-dimensional imaging genetics modules. Many of these modules are relevant to a variety of neurobiological pathways or neurodegenerative diseases, showing the promise of the proposal framework for providing insight into the mechanism of complex diseases.

Integrating Genetic, Neuropsychological and Neuroimaging Data to Model Early-Onset Obsessive Compulsive Disorder Severity.

We propose an integrative approach that combines structural magnetic resonance imaging data (MRI), diffusion tensor imaging data (DTI), neuropsychological data, and genetic data to predict early-onset obsessive compulsive disorder (OCD) severity. From a cohort of 87 patients, 56 with complete information were used in the present analysis. First, we performed a multivariate genetic association analysis of OCD severity with 266 genetic polymorphisms. This association analysis was used to select and prioritize the SNPs that would be included in the model. Second, we split the sample into a training set (N = 38) and a validation set (N = 18). Third, entropy-based measures of information gain were used for feature selection with the training subset. Fourth, the selected features were fed into two supervised methods of class prediction based on machine learning, using the leave-one-out procedure with the training set. Finally, the resulting model was validated with the validation set. Nine variables were used for the creation of the OCD severity predictor, including six genetic polymorphisms and three variables from the neuropsychological data. The developed model classified child and adolescent patients with OCD by disease severity with an accuracy of 0.90 in the testing set and 0.70 in the validation sample. Above its clinical applicability, the combination of particular neuropsychological, neuroimaging, and genetic characteristics could enhance our understanding of the neurobiological basis of the disorder.

FVGWAS: Fast voxelwise genome wide association analysis of large-scale imaging genetic data

More and more large-scale imaging genetic studies are being widely conducted to collect a rich set of imaging, genetic, and clinical data to detect putative genes for complexly inherited neuropsychiatric and neurodegenerative disorders. Several major big-data challenges arise from testing genome-wide (NC>12 million known variants) associations with signals at millions of locations (NV~106) in the brain from thousands of subjects (n~103). The aim of this paper is to develop a Fast Voxelwise Genome Wide Association analysiS (FVGWAS) framework to efficiently carry out whole-genome analyses of whole-brain data. FVGWAS consists of three components including a heteroscedastic linear model, a global sure independence screening (GSIS) procedure, and a detection procedure based on wild bootstrap methods. Specifically, for standard linear association, the computational complexity is O (nNVNC) for voxelwise genome wide association analysis (VGWAS) method compared with O ((NC+NV)n2) for FVGWAS. Simulation studies show that FVGWAS is an efficient method of searching sparse signals in an extremely large search space, while controlling for the family-wise error rate. Finally, we have successfully applied FVGWAS to a large-scale imaging genetic data analysis of ADNI data with 708 subjects, 193,275voxels in RAVENS maps, and 501,584 SNPs, and the total processing time was 203,645s for a single CPU. Our FVGWAS may be a valuable statistical toolbox for large-scale imaging genetic analysis as the field is rapidly advancing with ultra-high-resolution imaging and whole-genome sequencing.

Two-dimensional Enrichment Analysis for Mining High-level Imaging Genetic Associations.

Enrichment analysis has been widely applied in the genome-wide association studies (GWAS), where gene sets corresponding to biological pathways are examined for significant associations with a phenotype to help increase statistical power and improve biological interpretation. In this work, we expand the scope of enrichment analysis into brain imaging genetics, an emerging field that studies how genetic variation influences brain structure and function measured by neuroimaging quantitative traits (QT). Given the high dimensionality of both imaging and genetic data, we propose to study Imaging Genetic Enrichment Analysis (IGEA), a new enrichment analysis paradigm that jointly considers meaningful gene sets (GS) and brain circuits (BC) and examines whether any given GS-BC pair is enriched in a list of gene-QT findings. Using gene expression data from Allen Human Brain Atlas and imaging genetics data from Alzheimer's Disease Neuroimaging Initiative as test beds, we present an IGEA framework and conduct a proof-of-concept study. This empirical study identifies 12 significant high level two dimensional imaging genetics modules. Many of these modules are relevant to a variety of neurobiological pathways or neurodegenerative diseases, showing the promise of the proposal framework for providing insight into the mechanism of complex diseases.

FVGWAS: Fast voxelwise genome wide association analysis of large-scale imaging genetic data

FVGWAS: Fast voxelwise genome wide association analysis of large-scale imaging genetic data

GN-SCCA: GraphNet based Sparse Canonical Correlation Analysis for Brain Imaging Genetics.

Identifying associations between genetic variants and neuroimaging quantitative traits (QTs) is a popular research topic in brain imaging genetics. Sparse canonical correlation analysis (SCCA) has been widely used to reveal complex multi-SNP-multi-QT associations. Several SCCA methods explicitly incorporate prior knowledge into the model and intend to uncover the hidden structure informed by the prior knowledge. We propose a novel structured SCCA method using Graph constrained Elastic-Net (GraphNet) regularizer to not only discover important associations, but also induce smoothness between coefficients that are adjacent in the graph. In addition, the proposed method incorporates the covariance structure information usually ignored by most SCCA methods. Experiments on simulated and real imaging genetic data show that, the proposed method not only outperforms a widely used SCCA method but also yields an easy-to-interpret biological findings.

Comparison of variants of canonical correlation analysis and partial least squares for combined analysis of MRI and genetic data

The standard analysis approach in neuroimaging genetics studies is the mass-univariate linear modeling (MULM) approach. From a statistical view, however, this approach is disadvantageous, as it is computationally intensive, cannot account for complex multivariate relationships, and has to be corrected for multiple testing. In contrast, multivariate methods offer the opportunity to include combined information from multiple variants to discover meaningful associations between genetic and brain imaging data. We assessed three multivariate techniques, partial least squares correlation (PLSC), sparse canonical correlation analysis (sparse CCA) and Bayesian inter-battery factor analysis (Bayesian IBFA), with respect to their ability to detect multivariate genotype–phenotype associations. Our goal was to systematically compare these three approaches with respect to their performance and to assess their suitability for high-dimensional and multi-collinearly dependent data as is the case in neuroimaging genetics studies. In a series of simulations using both linearly independent and multi-collinear data, we show that sparse CCA and PLSC are suitable even for very high-dimensional collinear imaging data sets. Among those two, the predictive power was higher for sparse CCA when voxel numbers were below 400 times sample size and candidate SNPs were considered. Accordingly, we recommend Sparse CCA for candidate phenotype, candidate SNP studies. When voxel numbers exceeded 500 times sample size, the predictive power was the highest for PLSC. Therefore, PLSC can be considered a promising technique for multivariate modeling of high-dimensional brain–SNP-associations. In contrast, Bayesian IBFA cannot be recommended, since additional post-processing steps were necessary to detect causal relations. To verify the applicability of sparse CCA and PLSC, we applied them to an experimental imaging genetics data set provided for us. Most importantly, application of both methods replicated the findings of this data set.

Transcriptome-guided amyloid imaging genetic analysis via a novel structured sparse learning algorithm.

Motivation: Imaging genetics is an emerging field that studies the influence of genetic variation on brain structure and function. The major task is to examine the association between genetic markers such as single-nucleotide polymorphisms (SNPs) and quantitative traits (QTs) extracted from neuroimaging data. The complexity of these datasets has presented critical bioinformatics challenges that require new enabling tools. Sparse canonical correlation analysis (SCCA) is a bi-multivariate technique used in imaging genetics to identify complex multi-SNP–multi-QT associations. However, most of the existing SCCA algorithms are designed using the soft thresholding method, which assumes that the input features are independent from one another. This assumption clearly does not hold for the imaging genetic data. In this article, we propose a new knowledge-guided SCCA algorithm (KG-SCCA) to overcome this limitation as well as improve learning results by incorporating valuable prior knowledge.Results: The proposed KG-SCCA method is able to model two types of prior knowledge: one as a group structure (e.g. linkage disequilibrium blocks among SNPs) and the other as a network structure (e.g. gene co-expression network among brain regions). The new model incorporates these prior structures by introducing new regularization terms to encourage weight similarity between grouped or connected features. A new algorithm is designed to solve the KG-SCCA model without imposing the independence constraint on the input features. We demonstrate the effectiveness of our algorithm with both synthetic and real data. For real data, using an Alzheimer’s disease (AD) cohort, we examine the imaging genetic associations between all SNPs in the APOE gene (i.e. top AD gene) and amyloid deposition measures among cortical regions (i.e. a major AD hallmark). In comparison with a widely used SCCA implementation, our KG-SCCA algorithm produces not only improved cross-validation performances but also biologically meaningful results.Availability: Software is freely available on request.Contact: shenli@iu.edu

DRD2/ANKK1 polymorphism modulates the effect of ventral striatal activation on working memory performance.

Motivation is important for learning and cognition. Although dopaminergic (D2) transmission in the ventral striatum (VS) is associated with motivation, learning, and cognition are more strongly associated with function of the dorsal striatum, including activation in the caudate nucleus. A recent study found an interaction between intrinsic motivation and the DRD2/ANKK1 polymorphism (rs1800497), suggesting that A-carriers of rs1800497 are significantly more sensitive to motivation in order to improve during working memory (WM) training. Using data from the two large-scale imaging genetic data sets, IMAGEN (n=1080, age 13-15 years) and BrainChild (n∼300, age 6-27), we investigated whether rs1800497 is associated with WM. In the IMAGEN data set, we tested whether VS/caudate activation during reward anticipation was associated with WM performance and whether rs1800497 and VS/caudate activation interact to affect WM performance. We found that rs1800497 was associated with WM performance in IMAGEN and BrainChild. Higher VS and caudate activation during reward processing were significantly associated with higher WM performance (p<0.0001). An interaction was found between the DRD2/ANKK1 polymorphism rs1800497 and VS activation during reward anticipation on WM (p<0.01), such that carriers of the minor allele (A) showed a significant correlation between VS activation and WM, whereas the GG-homozygotes did not, suggesting that the effect of VS BOLD on WM is modified by inter-individual genetic differences related to D2 dopaminergic transmission.

DATA SYNTHESIS AND METHOD EVALUATION FOR BRAIN IMAGING GENETICS.

Brain imaging genetics is an emergent research field where the association between genetic variations such as single nucleotide polymorphisms (SNPs) and neuroimaging quantitative traits (QTs) is evaluated. Sparse canonical correlation analysis (SCCA) is a bi-multivariate analysis method that has the potential to reveal complex multi-SNP-multi-QT associations. We present initial efforts on evaluating a few SCCA methods for brain imaging genetics. This includes a data synthesis method to create realistic imaging genetics data with known SNP-QT associations, application of three SCCA algorithms to the synthetic data, and comparative study of their performances. Our empirical results suggest, approximating covariance structure using an identity or diagonal matrix, an approach used in these SCCA algorithms, could limit the SCCA capability in identifying the underlying imaging genetics associations. An interesting future direction is to develop enhanced SCCA methods that effectively take into account the covariance structures in the imaging genetics data.

A review of multivariate analyses in imaging genetics.

Recent advances in neuroimaging technology and molecular genetics provide the unique opportunity to investigate genetic influence on the variation of brain attributes. Since the year 2000, when the initial publication on brain imaging and genetics was released, imaging genetics has been a rapidly growing research approach with increasing publications every year. Several reviews have been offered to the research community focusing on various study designs. In addition to study design, analytic tools and their proper implementation are also critical to the success of a study. In this review, we survey recent publications using data from neuroimaging and genetics, focusing on methods capturing multivariate effects accommodating the large number of variables from both imaging data and genetic data. We group the analyses of genetic or genomic data into either a priori driven or data driven approach, including gene-set enrichment analysis, multifactor dimensionality reduction, principal component analysis, independent component analysis (ICA), and clustering. For the analyses of imaging data, ICA and extensions of ICA are the most widely used multivariate methods. Given detailed reviews of multivariate analyses of imaging data available elsewhere, we provide a brief summary here that includes a recently proposed method known as independent vector analysis. Finally, we review methods focused on bridging the imaging and genetic data by establishing multivariate and multiple genotype-phenotype-associations, including sparse partial least squares, sparse canonical correlation analysis, sparse reduced rank regression and parallel ICA. These methods are designed to extract latent variables from both genetic and imaging data, which become new genotypes and phenotypes, and the links between the new genotype-phenotype pairs are maximized using different cost functions. The relationship between these methods along with their assumptions, advantages, and limitations are discussed.

A novel structure-aware sparse learning algorithm for brain imaging genetics.

Brain imaging genetics is an emergent research field where the association between genetic variations such as single nucleotide polymorphisms (SNPs) and neuroimaging quantitative traits (QTs) is evaluated. Sparse canonical correlation analysis (SCCA) is a bi-multivariate analysis method that has the potential to reveal complex multi-SNP-multi-QT associations. Most existing SCCA algorithms are designed using the soft threshold strategy, which assumes that the features in the data are independent from each other. This independence assumption usually does not hold in imaging genetic data, and thus inevitably limits the capability of yielding optimal solutions. We propose a novel structure-aware SCCA (denoted as S2CCA) algorithm to not only eliminate the independence assumption for the input data, but also incorporate group-like structure in the model. Empirical comparison with a widely used SCCA implementation, on both simulated and real imaging genetic data, demonstrated that S2CCA could yield improved prediction performance and biologically meaningful findings.

An Integrative Bayesian Modeling Approach to Imaging Genetics

In this article we present a Bayesian hierarchical modeling approach for imaging genetics, where the interest lies in linking brain connectivity across multiple individuals to their genetic information. We have available data from a functional magnetic resonance imaging (fMRI) study on schizophrenia. Our goals are to identify brain regions of interest (ROIs) with discriminating activation patterns between schizophrenic patients and healthy controls, and to relate the ROIs’ activations with available genetic information from single nucleotide polymorphisms (SNPs) on the subjects. For this task, we develop a hierarchical mixture model that includes several innovative characteristics: it incorporates the selection of ROIs that discriminate the subjects into separate groups; it allows the mixture components to depend on selected covariates; it includes prior models that capture structural dependencies among the ROIs. Applied to the schizophrenia dataset, the model leads to the simultaneous selection of a set of discriminatory ROIs and the relevant SNPs, together with the reconstruction of the correlation structure of the selected regions. To the best of our knowledge, our work represents the first attempt at a rigorous modeling strategy for imaging genetics data that incorporates all such features.

Identifying disease sensitive and quantitative trait-relevant biomarkers from multidimensional heterogeneous imaging genetics data via sparse multimodal multitask learning

Motivation: Recent advances in brain imaging and high-throughput genotyping techniques enable new approaches to study the influence of genetic and anatomical variations on brain functions and disorders. Traditional association studies typically perform independent and pairwise analysis among neuroimaging measures, cognitive scores and disease status, and ignore the important underlying interacting relationships between these units.Results: To overcome this limitation, in this article, we propose a new sparse multimodal multitask learning method to reveal complex relationships from gene to brain to symptom. Our main contributions are three-fold: (i) introducing combined structured sparsity regularizations into multimodal multitask learning to integrate multidimensional heterogeneous imaging genetics data and identify multimodal biomarkers; (ii) utilizing a joint classification and regression learning model to identify disease-sensitive and cognition-relevant biomarkers; (iii) deriving a new efficient optimization algorithm to solve our non-smooth objective function and providing rigorous theoretical analysis on the global optimum convergency. Using the imaging genetics data from the Alzheimer's Disease Neuroimaging Initiative database, the effectiveness of the proposed method is demonstrated by clearly improved performance on predicting both cognitive scores and disease status. The identified multimodal biomarkers could predict not only disease status but also cognitive function to help elucidate the biological pathway from gene to brain structure and function, and to cognition and disease.Availability: Software is publicly available at: http://ranger.uta.edu/%7eheng/multimodal/Contact: heng@uta.edu; shenli@iupui.edu

Imaging Phenotypes and Genotypes in Schizophrenia

Schizophrenia is associated with subtle structural and functional brain abnormalities. Both recent and classical data suggest that it is a heterogeneous disorder that is clearly heritable. The cause and course of schizophrenia are poorly understood, and classical categories of clinical symptoms have not been particularly useful in identifying its pathophysiology or predicting its treatment. The possible genetic risk factors for schizophrenia are numerous; however, the connection between the genotype and the time-course, or the multifaceted symptoms of the disease, has yet to be established. Brain imaging methods that study the structure or function of the cortical and subcortical regions have also identified distinct patterns that distinguish schizophrenics from controls, and that may identify meaningful subtypes of schizophrenia. The predictive relationship between these imaging phenotypes and disease characteristics such as treatment response is only beginning to be revealed. The emergence of the field of imaging genetics, combining genetic, and neuroimaging data, holds much promise for the deeper understanding and improved treatment of diseases such as schizophrenia. In this article we review some of the key findings in imaging phenotyping and genotyping of schizophrenia, and the initial endeavors at their combination into more meaningful and predictive patterns, or endophenotypes identifying the relationships among clinical symptoms, course, genes, and the underlying pathophysiology.