Imaging Genetic Associations Research Articles

Multi-Task Learning and Sparse Discriminant Canonical Correlation Analysis for Identification of Diagnosis-Specific Genotype-Phenotype Association.

The primary objective of imaging genetics research is to investigate the complex genotype-phenotype association for the disease under study. For example, to understand the impact of genetic variations over the brain functions and structure, the genotypic data such as single nucleotide polymorphism (SNP) is integrated with the phenotypic data such as imaging quantitative traits. The sparse models, based on canonical correlation analysis (CCA), are popular in this area to find the complex bi-multivariate genotype-phenotype association, as the number of features in genotypic and/or phenotypic data is significantly higher as compared to the number of samples. However, the sparse CCA based methods are, in general, unsupervised in nature, and fail to identify the diagnose-specific features those play an important role for the diagnosis and prognosis of the disease under study. In this regard, a new supervised model is proposed to study the complex genotype-phenotype association, by judiciously integrating the merits of CCA, linear discriminant analysis (LDA) and multi-task learning. The proposed model can identify the diagnose-specific as well as the diagnose-consistent features with significantly lower computational complexity. The performance of the proposed method, along with a comparison with the state-of-the-art methods, is evaluated on several synthetic data sets and one real imaging genetics data collected from Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. In the current study, the SNP as genetic data and resting state functional MRI ( fMRI) as imaging data are integrated to find the complex genotype-phenotype association. An important finding is that the proposed method has better correlation value, improved noise resistance and stability, and also has better feature selection ability. All the results illustrate the power and capability of the proposed method to find the diagnostic group-specific imaging genetic association, which may help to understand the neurodegenerative disorder in a more comprehensive way.

Deep self-reconstruction driven joint nonnegative matrix factorization model for identifying multiple genomic imaging associations in complex diseases

ObjectiveComprehensive analysis of histopathology images and transcriptomics data enables the identification of candidate biomarkers and multimodal association patterns. Most existing multimodal data association studies are derived from extensions of the joint nonnegative matrix factorization model for identifying complex data associations, which can make full use of clinical prior information. However, the raw data were usually taken as the input without considering the underlying complex multi-subspace structure, influencing the subsequent integration analysis results. MethodsThis study proposed a deep-self reconstructed joint nonnegative matrix factorization (DSRJNMF) model to use self-expressive properties to reconstruct the raw data to characterize the similarity structure associated with clinical labels. Then, the sparsity, orthogonality, and regularization constraints constructed from prior information are added to the DSRJNMF model to determine the sparse set of biologically relevant features across modalities. ResultsThe algorithm has been applied to identify the imaging genetic association of triple negative breast cancer (TNBC). Multilevel experimental results demonstrate that the proposed algorithm better estimates potential associations between pathological image features and miRNA-gene and identifies consistent multimodal imaging genetic biomarkers to guide the interpretation of TNBC. ConclusionThe propose method provides a novel idea of data association analysis oriented to complex diseases.

Preference matrix guided sparse canonical correlation analysis for mining brain imaging genetic associations in Alzheimer's disease.

Investigating the relationship between genetic variation and phenotypic traits is a key issue in quantitative genetics. Specifically for Alzheimer's disease, the association between genetic markers and quantitative traits remains vague while, once identified, will provide valuable guidance for the study and development of genetics-based treatment approaches. Currently, to analyze the association of two modalities, sparse canonical correlation analysis (SCCA) is commonly used to compute one sparse linear combination of the variable features for each modality, giving a pair of linear combination vectors in total that maximizes the cross-correlation between the analyzed modalities. One drawback of the plain SCCA model is that the existing findings and knowledge cannot be integrated into the model as priors to help extract interesting correlations as well as identify biologically meaningful genetic and phenotypic markers. To bridge this gap, we introduce preference matrix guided SCCA (PM-SCCA) that not only takes priors encoded as a preference matrix but also maintains computational simplicity. A simulation study and a real-data experiment are conducted to investigate the effectiveness of the model. Both experiments demonstrate that the proposed PM-SCCA model can capture not only genotype-phenotype correlation but also relevant features effectively.

Fused multi‐modal similarity network as prior in guiding brain imaging genetic association

AbstractBackgroundBrain imaging genetics aims to explore the genetic architecture underlying brain structure and functions. Recent studies showed that incorporation of prior knowledge, such as subject diagnosis information and brain regional correlation, can help identify significantly stronger imaging genetic associations. However, sometimes such information may be incomplete or even unavailable. In this project, we explore a new data‐driven prior knowledge that captures the subject‐level similarity matrix derived from fusion of multi‐modal similarity networks. It was built into the sparse canonical correlation analysis model, which is expected to identify brain imaging and genetic markers that contribute to the fused similarity matrix.MethodThe Amyloid and Tau imaging data were downloaded from the ADNI database. We have 800 and 291 subjects for amyloid and tau imaging respectively (Table. 1). SNPs with p<5×10−6 (n = 1080) were extracted from the large‐scale GWAS summary statistics from the IGAP. We built similarity networks for imaging and genetic data individually using normalized mutual information and then fused these network following (Fig. 1). Fused network was then applied as a prior knowledge in the discriminative sparse canonical correlation analysis (DSCCA) model. We also tested other prior knowledge in SCCA model for comparison including diagnosis group network and transcriptomic brain network. All methods were evaluated using ADNI genotype, amyloid and tau imaging data, where nested 5‐fold cross validation with the same set of training and test data was applied for fair comparison.ResultSCCA with fused network and diagnosis group showed better performances over others in both training and testing data set (Table. 2,3). In Fig. 2 are top 10 ROIs identified by SCCA with fused network, whose amyloid deposition are strongly associated with APOE SNP (rs429358). For tau, we identified left and right amygdala with tau accumulation strongly and consistently associated with rs429358 (fig.3).ConclusionAs prior knowledge incorporated into SCCA algorithm, fused similarity network can help improve the performance of imaging genetic association over traditional SCCA and that guided by the brain co‐expression network. It showed comparable performance as diagnosis information and thus could be a potential prior knowledge to consider when lack of diagnosis information.

Fused multi-modal similarity network as prior in guiding brain imaging genetic association.

Brain imaging genetics aims to explore the genetic architecture underlying brain structure and functions. Recent studies showed that the incorporation of prior knowledge, such as subject diagnosis information and brain regional correlation, can help identify significantly stronger imaging genetic associations. However, sometimes such information may be incomplete or even unavailable. In this study, we explore a new data-driven prior knowledge that captures the subject-level similarity by fusing multi-modal similarity networks. It was incorporated into the sparse canonical correlation analysis (SCCA) model, which is aimed to identify a small set of brain imaging and genetic markers that explain the similarity matrix supported by both modalities. It was applied to amyloid and tau imaging data of the ADNI cohort, respectively. Fused similarity matrix across imaging and genetic data was found to improve the association performance better or similarly well as diagnosis information, and therefore would be a potential substitute prior when the diagnosis information is not available (i.e., studies focused on healthy controls). Our result confirmed the value of all types of prior knowledge in improving association identification. In addition, the fused network representing the subject relationship supported by multi-modal data showed consistently the best or equally best performance compared to the diagnosis network and the co-expression network.

Incorporating multi-stage diagnosis status to mine associations between genetic risk variants and the multi-modality phenotype network in major depressive disorder

Depression (major depressive disorder, MDD) is a common and serious medical illness. Globally, it is estimated that 5% of adults suffer from depression. Recently, imaging genetics receives growing attention and become a powerful strategy for discoverying the associations between genetic variants (e.g., single-nucleotide polymorphisms, SNPs) and multi-modality brain imaging data. However, most of the existing MDD imaging genetic research studies conducted by clinicians usually utilize simple statistical analysis methods and only consider single-modality brain imaging, which are limited in the deeper discovery of the mechanistic understanding of MDD. It is therefore imperative to utilize a powerful and efficient technology to fully explore associations between genetic variants and multi-modality brain imaging. In this study, we developed a novel imaging genetic association framework to mine the multi-modality phenotype network between genetic risk variants and multi-stage diagnosis status. Specifically, the multi-modality phenotype network consists of voxel node features and connectivity edge features from structural magnetic resonance imaging (sMRI) and resting-state functional magnetic resonance imaging (rs-fMRI). Thereafter, an association model based on multi-task learning strategy was adopted to fully explore the relationship between the MDD risk SNP and the multi-modality phenotype network. The multi-stage diagnosis status was introduced to further mine the relation among the multiple modalities of different subjects. A multi-modality brain imaging data and genotype data were collected by us from two hospitals. The experimental results not only demonstrate the effectiveness of our proposed method but also identify some consistent and stable brain regions of interest (ROIs) biomarkers from the node and edge features of multi-modality phenotype network. Moreover, four new and potential risk SNPs associated with MDD were discovered.

Genetic impacts on nigral iron deposition in Parkinson's disease: A preliminary quantitative susceptibility mapping study.

Dysfunction of iron metabolism, especially in substantia nigra (SN), is widely acknowledged in Parkinson's disease (PD), but the genetic influence on iron deposition remains largely unknown. Thus, in this study, we aimed to investigate potential genetic impacts on iron deposition in PD. Seventy-four subjects, including 38 patients with PD and 36 age-matched normal controls, participated in this study. Imaging genetic association analysis was used to identify the specific influence of single nucleotide polymorphism (SNP) on iron-related quantitative traits (QT). Genetic effects on iron deposition at the disease level, SNP level, and their interactive effect were highlighted. Four strong SNP-QT associations were detected: rs602201-susceptibility of bilateral SN, rs198440-susceptibility of left SN, and rs7895403-susceptibility of left caudate head. Detailed analyses showed that: (1) significant iron deposition was exclusively found in bilateral SN in PD; (2) altered polymorphisms of the A allele/A- genotype of rs602201 and G allele/G- genotype of rs198440 and rs7895403 were more frequently observed in PD; (3) for rs602201, among all subjects, A- genotype carriers showed significantly increased iron content than TT genotype in bilateral SN; for rs198440 and rs7895403, G- carriers showed increased iron content than AA genotype in left SN and left caudate head, respectively; and (4) rs602201 exhibited significant SNP-by-disease interaction in bilateral SN. This study shows that rs602201 and rs198440 have a stimulative impact on nigral iron deposition in PD, which provides improved understanding of iron-related pathogenesis in PD, and specifically, that vulnerability to iron deposition in SN is genetic-based.

Imaging genetic association analysis of triple-negative breast cancer based on the integration of prior sample information.

Triple-negative breast cancer (TNBC) is one of the more aggressive subtypes of breast cancer. The prognosis of TNBC patients remains low. Therefore, there is still a need to continue identifying novel biomarkers to improve the prognosis and treatment of TNBC patients. Research in recent years has shown that the effective use and integration of information in genomic data and image data will contribute to the prediction and prognosis of diseases. Considering that imaging genetics can deeply study the influence of microscopic genetic variation on disease phenotype, this paper proposes a sample prior information-induced multidimensional combined non-negative matrix factorization (SPID-MDJNMF) algorithm to integrate the Whole-slide image (WSI), mRNAs expression data, and miRNAs expression data. The algorithm effectively fuses high-dimensional data of three modalities through various constraints. In addition, this paper constructs an undirected graph between samples, uses an adjacency matrix to constrain the similarity, and embeds the clinical stage information of patients in the algorithm so that the algorithm can identify the co-expression patterns of samples with different labels. We performed univariate and multivariate Cox regression analysis on the mRNAs and miRNAs in the screened co-expression modules to construct a TNBC-related prognostic model. Finally, we constructed prognostic models for 2-mRNAs (IL12RB2 and CNIH2) and 2-miRNAs (miR-203a-3p and miR-148b-3p), respectively. The prognostic model can predict the survival time of TNBC patients with high accuracy. In conclusion, our proposed SPID-MDJNMF algorithm can efficiently integrate image and genomic data. Furthermore, we evaluated the prognostic value of mRNAs and miRNAs screened by the SPID-MDJNMF algorithm in TNBC, which may provide promising targets for the prognosis of TNBC patients.

Multigraph Cluster Analysis of AD Candidate Genes via Human Brain Mapping

AbstractBackgroundBrain imaging genetics examines associations between imaging quantitative traits (QTs) and genetic factors such as single nucleotide polymorphisms (SNPs) to provide important insights into the pathogenesis of Alzheimer’s diseases (AD). Given the high dimensionality, the individual level SNP‐QT signals typically have small effect sizes and are hard to be detected and replicated. To overcome this limitation, this work proposes a new approach to identify high‐level imaging genetic associations through applying multi‐graph clustering to SNP‐QT association maps.MethodsParticipants include 255 cognitive normal (CN) and 218 late mild cognitive impairment (LMCI) subjects from the ADNI data. Linear regression is performed to regress regional AV‐45 measures on each of the 54 AD SNPs to obtain a brain association map across 116 AAL‐ROIs. To quantify the similarity between each SNP pair, 5 scoring functions are used to calculate 5 different similarity measures between the respective brain maps of the two SNPs. Each scoring function yields a similarity graph of all 54 SNPs. Multigraph min‐max clustering is applied to 5 different graphs simultaneously to group similar SNPs together. Functional annotation is performed on each SNP cluster and the corresponding average brain association map to provide high level interpretations.ResultsFigure 1 shows the genetic effect on regional AV‐45 measures for each pair of SNP and ROI. The multi‐graph clustering result is shown in Figure 2, where 54 AD‐related SNPs are clustered into two groups. Figure 3a shows the results of Enrichr Elsevier pathway analysis. SNP group 1 is associated with pathways such as amyloid beta clearance, while SNP group 2 is associated with pathways including amyloid beta formation and APP processing in AD. Figure 3b shows the NeuroSynth annotation of the average brain effect maps associated with the two SNP clusters, respectively.ConclusionWe proposed an approach that transforms individual level imaging genetic associations (SNP vs ROI) to high‐level associations (i.e., SNP cluster vs brain association map), and applied it to an LMCI study. These high‐level findings have the potential to provide valuable insights into relevant genetic pathways and brain circuits, which can help form new hypotheses for more detailed imaging and genetics studies in independent cohorts.

Mining High-Level Imaging Genetic Associations via Clustering AD Candidate Variants with Similar Brain Association Patterns.

Brain imaging genetics examines associations between imaging quantitative traits (QTs) and genetic factors such as single nucleotide polymorphisms (SNPs) to provide important insights into the pathogenesis of Alzheimer’s disease (AD). The individual level SNP-QT signals are high dimensional and typically have small effect sizes, making them hard to be detected and replicated. To overcome this limitation, this work proposes a new approach that identifies high-level imaging genetic associations through applying multigraph clustering to the SNP-QT association maps. Given an SNP set and a brain QT set, the association between each SNP and each QT is evaluated using a linear regression model. Based on the resulting SNP-QT association map, five SNP–SNP similarity networks (or graphs) are created using five different scoring functions, respectively. Multigraph clustering is applied to these networks to identify SNP clusters with similar association patterns with all the brain QTs. After that, functional annotation is performed for each identified SNP cluster and its corresponding brain association pattern. We applied this pipeline to an AD imaging genetic study, which yielded promising results. For example, in an association study between 54 AD SNPs and 116 amyloid QTs, we identified two SNP clusters with one responsible for amyloid beta clearances and the other regulating amyloid beta formation. These high-level findings have the potential to provide valuable insights into relevant genetic pathways and brain circuits, which can help form new hypotheses for more detailed imaging and genetics studies in independent cohorts.

Identify connectome between genotypes and brain network phenotypes via deep self-reconstruction sparse canonical correlation analysis.

As a rising research topic, brain imaging genetics aims to investigate the potential genetic architecture of both brain structure and function. It should be noted that in the brain, not all variations are deservedly caused by genetic effect, and it is generally unknown which imaging phenotypes are promising for genetic analysis. In this work, genetic variants (i.e. the single nucleotide polymorphism, SNP) can be correlated with brain networks (i.e. quantitative trait, QT), so that the connectome (including the brain regions and connectivity features) of functional brain networks from the functional magnetic resonance imaging data is identified. Specifically, a connection matrix is firstly constructed, whose upper triangle elements are selected to be connectivity features. Then, the PageRank algorithm is exploited for estimating the importance of different brain regions as the brain region features. Finally, a deep self-reconstruction sparse canonical correlation analysis (DS-SCCA) method is developed for the identification of genetic associations with functional connectivity phenotypic markers. This approach is a regularized, deep extension, scalable multi-SNP-multi-QT method, which is well-suited for applying imaging genetic association analysis to the Alzheimer's Disease Neuroimaging Initiative datasets. It is further optimized by adopting a parametric approach, augmented Lagrange and stochastic gradient descent. Extensive experiments are provided to validate that the DS-SCCA approach realizes strong associations and discovers functional connectivity and brain region phenotypic biomarkers to guide disease interpretation. The Matlab code is available at https://github.com/meimeiling/DS-SCCA/tree/main. Supplementary data are available at Bioinformatics online.

Identifying imaging genetics biomarkers in Alzheimer’s disease via integrating graph convolutional neural network and canonical correlation analysis

AbstractBackgroundBrain imaging genetics is an emerging research topic in the study of Alzheimer’s disease (AD). The conventional approach, such as canonical correlation analysis (CCA), has been widely used to identify imaging genetic associations. A deep learning model has recently been proposed to better understand the roots of the complex association between imaging and genetic measures. We propose a graph convolutional neural network (GCN) with CCA loss function to integrate and identify the complex imaging genetics associations in AD.MethodWe proposed a spectral GCN approach with CCA loss function (GCN‐CCA) to extract feature representations from imaging and genetics data. Briefly, the graph embeddings on the graph nodes were filtered in the Fourier domain. We used two hidden layers with 64 hidden units for extracting imaging and genetic data. ReLU activations were used after each graph convolution layer. A canonical correlation loss function was optimized based on Adam optimizer. We compared our model with the deep CCA model (DCCA) for AD classification.ResultWe downloaded data for 310 participants (103 AD and 207 Cognitive Normal [CN]) including neuroimaging and genetic data from the ADNI database. We used average structural connectivity based on the AAL atlas as the graph in our GCN model, three imaging measurements (VBM, FDG, FBR) as initial attributes on the graph nodes. We selected 2,644 candidate SNPs from the GWAS catalog (https://www.ebi.ac.uk/gwas/). The proposed model obtained 82.25 % test accuracy for the AD/CN classification, outperforming the DCCA model (77.41%). For interpretation, we generated the saliency maps using guided gradient backpropagation (Figs 1 and 2). We observed the imaging phenotypes from left middle temporal gyrus, superior temporal, frontal inferior triangularis, putamen, paracentral lobule, frontal medial orbital, and pallidum, and right posterior cingulum, and genetic markers from ABCA13 (rs2163935, rs6955132, rs4024044) and APOE (rs429358) contributed to the AD outcome prediction.ConclusionHere, we demonstrated the utility of GCN‐CCA model and its interpretability. The GCN‐CCA not only obtained higher prediction performance but also highlighted important regions for AD classification. We plan to apply our algorithm to other AD cohorts to see if our algorithm generalizes to independent data sets.

Identify Complex Imaging Genetic Patterns via Fusion Self-Expressive Network Analysis.

In the brain imaging genetic studies, it is a challenging task to estimate the association between quantitative traits (QTs) extracted from neuroimaging data and genetic markers such as single-nucleotide polymorphisms (SNPs). Most of the existing association studies are based on the extensions of sparse canonical correlation analysis (SCCA) for the identification of complex bi-multivariate associations, which can take the specific structure and group information into consideration. However, they often take the original data as input without considering its underlying complex multi-subspace structure, which will deteriorate the performance of the following integrative analysis. Accordingly, in this paper, the self-expressive property is exploited for the reconstruction of the original data before the association analysis, which can well describe the similarity structure. Specifically, we first apply the within-class similarity information to construct self-expressive networks by sparse representation. Then, we use the fusion method to iteratively fuse the self-expressive networks from multi-modality brain phenotypes into one network. Finally, we calculate the imaging genetic association based on the fused self-expressive network. We conduct the experiments on both single-modality and multi-modality phenotype data. Related experimental results validate that our method can not only better estimate the potential association between genetic markers and quantitative traits but also identify consistent multi-modality imaging genetic biomarkers to guide the interpretation of Alzheimer's disease.

Mapping the Interactive Effects of ApoE Gene Polymorphism on Caudate Functional Connectivity in Mild Cognitive Impairment Associated With Parkinson's Disease.

IntroductionCognitive impairment (CI) is a frequent non-motor symptom of Parkinson’s disease (PD). Caudate and Apolipoprotein E (ApoE) are biomarkers linked to CI in PD. There is little known about whether ApoE affects caudate in mild CI of PD (PD-MCI). We investigated the possible interactive effect of ApoE genotypes on caudate functional connectivity (FC) in PD-MCI.MethodsA total of 95 PD-MCI patients and 99 matched healthy controls underwent extensive neuropsychological assessment and magnetic resonance imaging. The two groups were separated into three subgroups according to their genotyping. Functional data were analyzed with FC analysis.ResultsDecreased FC between the caudate and the bilateral inferior orbit frontal gyrus and bilateral middle occipital gyrus (MOG) was found between groups, along with poor performance in general, executive, episodic memory, language, and visual–spatial function. Decreased FC between the caudate and right MOG, right middle temporal gyrus, and right superior occipital gyrus was found as an interaction effect. The FC values of ε4 carriers with PD-MCI were much lower than the other carriers, and FC was positively correlated with the impairment of global and language function.ConclusionThese results support the idea that altered FC between the bilateral caudate and posterior cortical regions was interactively influenced by ApoE genotype and PD-MCI status, and the ε4 subtype associated with underlying pathology of global cognitive decline and semantic fluency impairment in an interactive manner. Gene-based imaging approaches might strengthen the credibility in imaging genetic associations, which might provide new powerful insights into the neural mechanisms underlying PD-MCI.

Detecting genetic associations with brain imaging phenotypes in Alzheimer's disease via a novel structured SCCA approach.

Brain imaging genetics becomes an important research topic since it can reveal complex associations between genetic factors and the structures or functions of the human brain. Sparse canonical correlation analysis (SCCA) is a popular bi-multivariate association identification method. To mine the complex genetic basis of brain imaging phenotypes, there arise many SCCA methods with a variety of norms for incorporating different structures of interest. They often use the group lasso penalty, the fused lasso or the graph/network guided fused lasso ones. However, the group lasso methods have limited capability because of the incomplete or unavailable prior knowledge in real applications. The fused lasso and graph/network guided methods are sensitive to the sign of the sample correlation which may be incorrectly estimated. In this paper, we introduce two new penalties to improve the fused lasso and the graph/network guided lasso penalties in structured sparse learning. We impose both penalties to the SCCA model and propose an optimization algorithm to solve it. The proposed SCCA method has a strong upper bound of grouping effects for both positively and negatively highly correlated variables. We show that, on both synthetic and real neuroimaging genetics data, the proposed SCCA method performs better than or equally to the conventional methods using fused lasso or graph/network guided fused lasso. In particular, the proposed method identifies higher canonical correlation coefficients and captures clearer canonical weight patterns, demonstrating its promising capability in revealing biologically meaningful imaging genetic associations.

Regional imaging genetic enrichment analysis.

Brain imaging genetics aims to reveal genetic effects on brain phenotypes, where most studies examine phenotypes defined on anatomical or functional regions of interest (ROIs) given their biologically meaningful interpretation and modest dimensionality compared with voxelwise approaches. Typical ROI-level measures used in these studies are summary statistics from voxelwise measures in the region, without making full use of individual voxel signals. In this article, we propose a flexible and powerful framework for mining regional imaging genetic associations via voxelwise enrichment analysis, which embraces the collective effect of weak voxel-level signals and integrates brain anatomical annotation information. Our proposed method achieves three goals at the same time: (i) increase the statistical power by substantially reducing the burden of multiple comparison correction; (ii) employ brain annotation information to enable biologically meaningful interpretation and (iii) make full use of fine-grained voxelwise signals. We demonstrate our method on an imaging genetic analysis using data from the Alzheimer's Disease Neuroimaging Initiative, where we assess the collective regional genetic effects of voxelwise FDG-positron emission tomography measures between 116 ROIs and 565373 single-nucleotide polymorphisms. Compared with traditional ROI-wise and voxelwise approaches, our method identified 2946 novel imaging genetic associations in addition to 33 ones overlapping with the two benchmark methods. In particular, two newly reported variants were further supported by transcriptome evidences from region-specific expression analysis. This demonstrates the promise of the proposed method as a flexible and powerful framework for exploring imaging genetic effects on the brain. The R code and sample data are freely available at https://github.com/lshen/RIGEA. Supplementary data are available at Bioinformatics online.

Mapping causal pathways from genetics to neuropsychiatric disorders using genome-wide imaging genetics: Current status and future directions.

Imaging genetics aims to identify genetic variants associated with the structure and function of the human brain. Recently, collaborative consortia have been successful in this goal, identifying and replicating common genetic variants influencing gross human brain structure as measured through magnetic resonance imaging. In this review, we contextualize imaging genetic associations as one important link in understanding the causal chain from genetic variant to increased risk for neuropsychiatric disorders. We provide examples in other fields of how identifying genetic variant associations to disease and multiple phenotypes along the causal chain has revealed a mechanistic understanding of disease risk, with implications for how imaging genetics can be similarly applied. We discuss current findings in the imaging genetics research domain, including that common genetic variants can have a slightly larger effect on brain structure than on risk for disorders like schizophrenia, indicating a somewhat simpler genetic architecture. Also, gross brain structure measurements share a genetic basis with some, but not all, neuropsychiatric disorders, invalidating the previously held belief that they are broad endophenotypes, yet pinpointing brain regions likely involved in the pathology of specific disorders. Finally, we suggest that in order to build a more detailed mechanistic understanding of the effects of genetic variants on the brain, future directions in imaging genetics research will require observations of cellular and synaptic structure in specific brain regions beyond the resolution of magnetic resonance imaging. We expect that integrating genetic associations at biological levels from synapse to sulcus will reveal specific causal pathways impacting risk for neuropsychiatric disorders.

Mining Regional Imaging Genetic Associations via Voxel-wise Enrichment Analysis.

Brain imaging genetics aims to reveal genetic effects on brain phenotypes, where most studies examine phenotypes defined on anatomical or functional regions of interest (ROIs) given their biologically meaningful annotation and modest dimensionality compared with voxel-wise approaches. Typical ROI-level measures used in these studies are summary statistics from voxel-wise measures in the region, without making full use of individual voxel signals. In this paper, we propose a flexible and powerful framework for mining regional imaging genetic associations via voxel-wise enrichment analysis, which embraces the collective effect of weak voxel-level signals within an ROI. We demonstrate our method on an imaging genetic analysis using data from the Alzheimers Disease Neuroimaging Initiative, where we assess the collective regional genetic effects of voxel-wise FDGPET measures between 116 ROIs and 19 AD candidate SNPs. Compared with traditional ROI-wise and voxel-wise approaches, our method identified 102 additional significant associations, some of which were further supported by evidences in brain tissue-specific expression analysis. This demonstrates the promise of the proposed method as a flexible and powerful framework for exploring imaging genetic effects on the brain.

Distance canonical correlation analysis with application to an imaging-genetic study.

Distance correlation is a measure that can detect both linear and nonlinear associations. However, applying distance correlation to imaging genetic studies often needs multiple testing correction due to the large number of multiple inferences. As a result, the sensitivity of its detection may be low. We propose a new model, distance canonical correlation analysis (DCCA), which overcomes this problem by searching a combination of features with the highest distance correlation. This is achieved by constructing a distance kernel function followed by solving a subsequent optimization problem. The ability to detect both linear and nonlinear associations makes DCCA suitable for analyzing complex multimodal and imaging-genetic associations. When applied to a brain imaging-genetic study from the Philadelphia Neurodevelopmental Cohort (PNC), DCCA detected several mental disorder-related gene pathways and brain networks. Experiments on brain connectivity found that the default mode network had strong nonlinear connections with other brain networks. When applied to the study of age effects, DCCA revealed that the connections of brain networks were relatively weak in younger groups but became stronger at older age stages. It indicates that adolescence is a vital stage for brain development. DCCA thus reveals a number of interesting findings and demonstrates a powerful new approach for analyzing multimodal brain imaging data.

A framework for linking resting-state chronnectome/genome features in schizophrenia: A pilot study

Multimodal, imaging-genomics techniques offer a platform for understanding genetic influences on brain abnormalities in psychiatric disorders. Such approaches utilize the information available from both imaging and genomics data and identify their association. Particularly for complex disorders such as schizophrenia, the relationship between imaging and genomic features may be better understood by incorporating additional information provided by advanced multimodal modeling. In this study, we propose a novel framework to combine features corresponding to functional magnetic resonance imaging (functional) and single nucleotide polymorphism (SNP) data from 61 schizophrenia (SZ) patients and 87 healthy controls (HC). In particular, the features for the functional and genetic modalities include dynamic (i.e., time-varying) functional network connectivity (dFNC) features and the SNP data, respectively. The dFNC features are estimated from component time-courses, obtained using group independent component analysis (ICA), by computing sliding-window functional network connectivity, and then estimating subject specific states from this dFNC data using a k-means clustering approach. For each subject, both the functional (dFNC states) and SNP data are selected as features for a parallel ICA (pICA) based imaging-genomic framework. This analysis identified a significant association between a SNP component (defined by large clusters of functionally related SNPs statistically correlated with phenotype components) and time-varying or dFNC component (defined by clusters of related connectivity links among distant brain regions distributed across discrete dynamic states, and statistically correlated with genomic components) in schizophrenia. Importantly, the polygenetic risk score (PRS) for SZ (computed as a linearly weighted sum of the genotype profiles with weights derived from the odds ratios of the psychiatric genomics consortium (PGC)) was negatively correlated with the significant dFNC component, which were mostly present within a state that exhibited a lower occupancy rate in individuals with SZ compared with HC, hence identifying a potential dFNC imaging biomarker for schizophrenia. Taken together, the current findings provide preliminary evidence for a link between dFNC measures and genetic risk, suggesting the application of dFNC patterns as biomarkers in imaging genetic association study.