Modeling genotype-protein interaction and correlation for Alzheimer's disease: a multi-omics imaging genetics study.

Integrating and analyzing multiple omics data sets, including genomics, proteomics and radiomics, can significantly advance researchers' comprehensive understanding of Alzheimer's disease (AD). However, current methodologies primarily focus on the main effects of genetic variation and protein, overlooking non-additive effects such as genotype-protein interaction (GPI) and correlation patterns in brain imaging genetics studies. Importantly, these non-additive effects could contribute to intermediate imaging phenotypes, finally leading to disease occurrence. In general, the interaction between genetic variations and proteins, and their correlations are two distinct biological effects, and thus disentangling the two effects for heritable imaging phenotypes is of great interest and need. Unfortunately, this issue has been largely unexploited. In this paper, to fill this gap, we propose $\textbf{M}$ulti-$\textbf{T}$ask $\textbf{G}$enotype-$\textbf{P}$rotein $\textbf{I}$nteraction and $\textbf{C}$orrelation disentangling method ($\textbf{MT-GPIC}$) to identify GPI and extract correlation patterns between them. To ensure stability and interpretability, we use novel and off-the-shelf penalties to identify meaningful genetic risk factors, as well as exploit the interconnectedness of different brain regions. Additionally, since computing GPI poses a high computational burden, we develop a fast optimization strategy for solving MT-GPIC, which is guaranteed to converge. Experimental results on the Alzheimer's Disease Neuroimaging Initiative data set show that MT-GPIC achieves higher correlation coefficients and classification accuracy than state-of-the-art methods. Moreover, our approach could effectively identify interpretable phenotype-related GPI and correlation patterns in high-dimensional omics data sets. These findings not only enhance the diagnostic accuracy but also contribute valuable insights into the underlying pathogenic mechanisms of AD.

Identifying frequency-dependent imaging genetic associations via hypergraph-structured multi-task sparse canonical correlation analysis.

Identifying complex associations between genetic variations and imaging phenotypes is a challenging task in the research of brain imaging genetics. The previous study has proved that neuronal oscillations within distinct frequency bands are derived from frequency-dependent genetic modulation. Thus it is meaningful to explore frequency-dependent imaging genetic associations, which may give important insights into the pathogenesis of brain disorders. In this work, the hypergraph-structured multi-task sparse canonical correlation analysis (HS-MTSCCA) was developed to explore the associations between multi-frequency imaging phenotypes and single-nucleotide polymorphisms (SNPs). Specifically, we first created a hypergraph for the imaging phenotypes of each frequency and the SNPs, respectively. Then, a new hypergraph-structured constraint was proposed to learn high-order relationships among features in each hypergraph, which can introduce biologically meaningful information into the model. The frequency-shared and frequency-specific imaging phenotypes and SNPs could be identified using the multi-task learning framework. We also proposed a useful strategy to tackle this algorithm and then demonstrated its convergence. The proposed method was evaluated on four simulation datasets and a real schizophrenia dataset. The experimental results on synthetic data showed that HS-MTSCCA outperforms the other competing methods according to canonical correlation coefficients, canonical weights, and cosine similarity. And the results on real data showed that HS-MTSCCA could obtain superior canonical coefficients and canonical weights. Furthermore, the identified frequency-shared and frequency-specific biomarkers could provide more interesting and meaningful information, demonstrating that HS-MTSCCA is a powerful method for brain imaging genetics.

inMTSCCA: An Integrated Multi-task Sparse Canonical Correlation Analysis for Multi-omic Brain Imaging Genetics.

Identifying genetic risk factors for Alzheimer's disease (AD) is an important research topic. To date, different endophenotypes, such as imaging-derived endophenotypes and proteomic expression-derived endophenotypes, have shown the great value in uncovering risk genes compared to case-control studies. Biologically, a co-varying pattern of different omics-derived endophenotypes could result from the shared genetic basis. However, existing methods mainly focus on the effect of endophenotypes alone; the effect of cross-endophenotype (CEP) associations remains largely unexploited. In this study, we used both endophenotypes and their CEP associations of multi-omic data to identify genetic risk factors, and proposed two integrated multi-task sparse canonical correlation analysis (inMTSCCA) methods, i.e., pairwise endophenotype correlation-guided MTSCCA (pcMTSCCA) and high-order endophenotype correlation-guided MTSCCA (hocMTSCCA). pcMTSCCA employed pairwise correlations between magnetic resonance imaging (MRI)-derived, plasma-derived, and cerebrospinal fluid (CSF)-derived endophenotypes as an additional penalty. hocMTSCCA used high-order correlations among these multi-omic data for regularization. To figure out genetic risk factors at individual and group levels, as well as altered endophenotypic markers, we introduced sparsity-inducing penalties for both models. We compared pcMTSCCA and hocMTSCCA with three related methods on both simulation and real (consisting of neuroimaging data, proteomic analytes, and genetic data) datasets. The results showed that our methods obtained better or comparable canonical correlation coefficients (CCCs) and better feature subsets than benchmarks. Most importantly, the identified genetic loci and heterogeneous endophenotypic markers showed high relevance. Therefore, jointly using multi-omic endophenotypes and their CEP associations is promising to reveal genetic risk factors. The source code and manual of inMTSCCA are available at https://ngdc.cncb.ac.cn/biocode/tools/BT007330.

Hypergraph-regularized multimodal learning by graph diffusion for imaging genetics based Alzheimer's Disease diagnosis.

Recent studies show that multi-modal data fusion techniques combining information from diverse sources are helpful to diagnose and predict complex brain disorders. However, most existing diagnosis methods have only simply employed a feature combination strategy for multiple imaging and genetic data, ignoring the imaging phenotypes associated with the risk gene information. To this end, we present a hypergraph-regularized multimodal learning by graph diffusion (HMGD) for joint association learning and outcome prediction. Specifically, we first present a graph diffusion method for enhancing similarity measures among subjects given from multi-modality phenotypes, which fully uses multiple input similarity graphs and integrates them into a unified graph with valuable geometric structures among different imaging phenotypes. Then, we employ the unified graph to represent the high-order similarity relationships among subjects, and enforce a hypergraph-regularized term to incorporate both inter- and cross-modality information for selecting the imaging phenotypes associated with the risk single nucleotide polymorphism (SNP). Finally, a multi-kernel support vector machine (MK-SVM) is adopted to fuse such phenotypic features selected from different modalities for the final diagnosis and prediction. The proposed approach is experimentally explored on brain imaging genetic data of the Alzheimer's Disease Neuroimaging Initiative (ADNI) datasets. Relevant results present that the proposed approach is superior to several competing algorithms, and realizes strong associations and discovers significant consistent and robust ROIs across different imaging phenotypes associated with the genetic risk biomarkers to guide disease interpretation and prediction.

A Novel Longitudinal Phenotype-Genotype Association Study Based on Deep Feature Extraction and Hypergraph Models for Alzheimer's Disease.

Traditional image genetics primarily uses linear models to investigate the relationship between brain image data and genetic data for Alzheimer's disease (AD) and does not take into account the dynamic changes in brain phenotype and connectivity data across time between different brain areas. In this work, we proposed a novel method that combined Deep Subspace reconstruction with Hypergraph-Based Temporally-constrained Group Sparse Canonical Correlation Analysis (DS-HBTGSCCA) to discover the deep association between longitudinal phenotypes and genotypes. The proposed method made full use of dynamic high-order correlation between brain regions. In this method, the deep subspace reconstruction technique was applied to retrieve the nonlinear properties of the original data, and hypergraphs were used to mine the high-order correlation between two types of rebuilt data. The molecular biological analysis of the experimental findings demonstrated that our algorithm was capable of extracting more valuable time series correlation from the real data obtained by the AD neuroimaging program and finding AD biomarkers across multiple time points. Additionally, we used regression analysis to verify the close relationship between the extracted top brain areas and top genes and found the deep subspace reconstruction approach with a multi-layer neural network was helpful in enhancing clustering performance.

A multi-task SCCA method for brain imaging genetics and its application in neurodegenerative diseases.

BACKGROUND AND OBJECTIVES: In brain imaging genetics, multi-task sparse canonical correlation analysis (MTSCCA) is effective to study the bi-multivariate associations between genetic variations such as single nucleotide polymorphisms (SNPs) and multi-modal imaging quantitative traits (QTs). However, most existing MTSCCA methods are neither supervised nor capable of distinguishing the shared patterns of multi-modal imaging QTs from the specific patterns. METHODS: A new diagnosis-guided MTSCCA (DDG-MTSCCA) with parameter decomposition and graph-guided pairwise group lasso penalty was proposed. Specifically, the multi-tasking modeling paradigm enables us to comprehensively identify risk genetic loci by jointly incorporating multi-modal imaging QTs. The regression sub-task was raised to guide the selection of diagnosis-related imaging QTs. To reveal the diverse genetic mechanisms, the parameter decomposition and different constraints were utilized to facilitate the identification of modality-consistent and -specific genotypic variations. Besides, a network constraint was added to find out meaningful brain networks. The proposed method was applied to synthetic data and two real neuroimaging data sets respectively from Alzheimer's disease neuroimaging initiative (ADNI) and Parkinson's progression marker initiative (PPMI) databases. RESULTS: Compared with the competitive methods, the proposed method exhibited higher or comparable canonical correlation coefficients (CCCs) and better feature selection results. In particular, in the simulation study, DDG-MTSCCA showed the best anti-noise ability and achieved the highest average hit rate, about 25% higher than MTSCCA. On the real data of Alzheimer's disease (AD) and Parkinson's disease (PD), our method obtained the highest average testing CCCs, about 40% ∼ 50% higher than MTSCCA. Especially, our method could select more comprehensive feature subsets, and the top five SNPs and imaging QTs were all disease-related. The ablation experimental results also demonstrated the significance of each component in the model, i.e., the diagnosis guidance, parameter decomposition, and network constraint. CONCLUSIONS: These results on simulated data, ADNI and PPMI cohorts suggested the effectiveness and generalizability of our method in identifying meaningful disease-related markers. DDG-MTSCCA could be a powerful tool in brain imaging genetics, worthy of in-depth study.

A novel generation adversarial network framework with characteristics aggregation and diffusion for brain disease classification and feature selection.

Imaging genetics provides unique insights into the pathological studies of complex brain diseases by integrating the characteristics of multi-level medical data. However, most current imaging genetics research performs incomplete data fusion. Also, there is a lack of effective deep learning methods to analyze neuroimaging and genetic data jointly. Therefore, this paper first constructs the brain region-gene networks to intuitively represent the association pattern of pathogenetic factors. Second, a novel feature information aggregation model is constructed to accurately describe the information aggregation process among brain region nodes and gene nodes. Finally, a deep learning method called feature information aggregation and diffusion generative adversarial network (FIAD-GAN) is proposed to efficiently classify samples and select features. We focus on improving the generator with the proposed convolution and deconvolution operations, with which the interpretability of the deep learning framework has been dramatically improved. The experimental results indicate that FIAD-GAN can not only achieve superior results in various disease classification tasks but also extract brain regions and genes closely related to AD. This work provides a novel method for intelligent clinical decisions. The relevant biomedical discoveries provide a reliable reference and technical basis for the clinical diagnosis, treatment and pathological analysis of disease.

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.

Identifying genetic markers enriched by brain imaging endophenotypes in Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a complex neurodegenerative disorder and the most common type of dementia. AD is characterized by a decline of cognitive function and brain atrophy, and is highly heritable with estimated heritability ranging from 60 to 80[Formula: see text]. The most straightforward and widely used strategy to identify AD genetic basis is to perform genome-wide association study (GWAS) of the case-control diagnostic status. These GWAS studies have identified over 50 AD related susceptibility loci. Recently, imaging genetics has emerged as a new field where brain imaging measures are studied as quantitative traits to detect genetic factors. Given that many imaging genetics studies did not involve the diagnostic outcome in the analysis, the identified imaging or genetic markers may not be related or specific to the disease outcome. RESULTS: We propose a novel method to identify disease-related genetic variants enriched by imaging endophenotypes, which are the imaging traits associated with both genetic factors and disease status. Our analysis consists of three steps: (1) map the effects of a genetic variant (e.g., single nucleotide polymorphism or SNP) onto imaging traits across the brain using a linear regression model, (2) map the effects of a diagnosis phenotype onto imaging traits across the brain using a linear regression model, and (3) detect SNP-diagnosis association via correlating the SNP effects with the diagnostic effects on the brain-wide imaging traits. We demonstrate the promise of our approach by applying it to the Alzheimer's Disease Neuroimaging Initiative database. Among 54 AD related susceptibility loci reported in prior large-scale AD GWAS, our approach identifies 41 of those from a much smaller study cohort while the standard association approaches identify only two of those. Clearly, the proposed imaging endophenotype enriched approach can reveal promising AD genetic variants undetectable using the traditional method. CONCLUSION: We have proposed a novel method to identify AD genetic variants enriched by brain-wide imaging endophenotypes. This approach can not only boost detection power, but also reveal interesting biological pathways from genetic determinants to intermediate brain traits and to phenotypic AD outcomes.

Multi-task learning based structured sparse canonical correlation analysis for brain imaging genetics.

The advances in technologies for acquiring brain imaging and high-throughput genetic data allow the researcher to access a large amount of multi-modal data. Although the sparse canonical correlation analysis is a powerful bi-multivariate association analysis technique for feature selection, we are still facing major challenges in integrating multi-modal imaging genetic data and yielding biologically meaningful interpretation of imaging genetic findings. In this study, we propose a novel multi-task learning based structured sparse canonical correlation analysis (MTS2CCA) to deliver interpretable results and improve integration in imaging genetics studies. We perform comparative studies with state-of-the-art competing methods on both simulation and real imaging genetic data. On the simulation data, our proposed model has achieved the best performance in terms of canonical correlation coefficients, estimation accuracy, and feature selection accuracy. On the real imaging genetic data, our proposed model has revealed promising features of single-nucleotide polymorphisms and brain regions related to sleep. The identified features can be used to improve clinical score prediction using promising imaging genetic biomarkers. An interesting future direction is to apply our model to additional neurological or psychiatric cohorts such as patients with Alzheimer's or Parkinson's disease to demonstrate the generalizability of our method.

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

Neuroimaging genetics has become an important research topic since it can reveal complex associations between genetic variants (i.e. single nucleotide polymorphisms (SNPs) and the structures or functions of the human brain. However, existing kernel mapping is difficult to directly use the sparse representation method in the kernel feature space, which makes it difficult for most existing sparse canonical correlation analysis (SCCA) methods to be directly promoted in the kernel feature space. To bridge this gap, we adopt a novel alternating projected gradient approach, gradient KCCA (gradKCCA) model to develop a powerful model for exploring the intrinsic associations among genetic markers, imaging quantitative traits (QTs) of interest. Specifically, this model solves kernel canonical correlation (KCCA) with an additional constraint that projection directions have pre-images in the original data space, a sparsity-inducing variant of the model is achieved through controlling the [Formula: see text]-norm of the preimages of the projection directions. We evaluate this model using Alzheimer's disease Neuroimaging Initiative (ADNI) cohort to discover the relationships among SNPs from Alzheimer's disease (AD) risk gene APOE, imaging QTs extracted from structural magnetic resonance imaging (MRI) scans. Our results show that the algorithm not only outperforms the traditional KCCA method in terms of Root Mean Square Error (RMSE) and Correlation Coefficient (CC) but also identify the meaningful and relevant biomarkers of SNPs (e.g. rs157594 and rs405697), which are positively related to right Postcentral and right SupraMarginal brain regions in this study. Empirical results indicate its promising capability in revealing biologically meaningful neuroimaging genetics associations and improving the disease-related mechanistic understanding of AD.

An Improved Fusion Paired Group Lasso Structured Sparse Canonical Correlation Analysis Based on Brain Imaging Genetics to Identify Biomarkers of Alzheimer's Disease.

Brain imaging genetics can demonstrate the complicated relationship between genetic factors and the structure or function of the humankind brain. Therefore, it has become an important research topic and attracted more and more attention from scholars. The structured sparse canonical correlation analysis (SCCA) model has been widely used to identify the association between brain image data and genetic data in imaging genetics. To investigate the intricate genetic basis of cerebrum imaging phenotypes, a great deal of other standard SCCA methods combining different interested structed have now appeared. For example, some models use group lasso penalty, and some use the fused lasso or the graph/network guided fused lasso for feature selection. However, prior knowledge may not be completely available and the group lasso methods have limited capabilities in practical applications. The graph/network guided approaches can use sample correlation to define constraints, thereby overcoming this problem. Unfortunately, this also has certain limitations. The graph/network conducted methods are susceptible to the sign of the sample correlation of the data, which will affect the stability of the model. To improve the efficiency and stability of SCCA, a sparse canonical correlation analysis model with GraphNet regularization (FGLGNSCCA) is proposed in this manuscript. Based on the FGLSCCA model, the GraphNet regularization penalty is imposed in our study and an optimization algorithm is presented to optimize the model. The structural Magnetic Resonance Imaging (sMRI) and gene expression data are used in this study to find the genotype and characteristics of brain regions associated with Alzheimer's disease (AD). Experiment results shown that the new FGLGNSCCA model proposed in this manuscript is superior or equivalent to traditional methods in both artificially synthesized neuroimaging genetics data or actual neuroimaging genetics data. It can select essential features more powerfully compared with other multivariate methods and identify significant canonical correlation coefficients as well as captures more significant typical weight patterns which demonstrated its excellent ability in finding biologically important imaging genetic relations.

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.

DIAGNOSIS STATUS GUIDED BRAIN IMAGING GENETICS VIA INTEGRATED REGRESSION AND SPARSE CANONICAL CORRELATION ANALYSIS.

Brain imaging genetics use the imaging quantitative traits (QTs) as intermediate endophenotypes to identify the genetic basis of the brain structure, function and abnormality. The regression and canonical correlation analysis (CCA) coupled with sparsity regularization are widely used in imaging genetics. The regression only selects relevant features for predictors. SCCA overcomes this but is unsupervised and thus could not make use of the diagnosis information. We propose a novel method integrating regression and SCCA together to construct a supervised sparse bi-multivariate learning model. The regression part plays a role of providing guidance for imaging QTs selection, and the SCCA part is focused on selecting relevant genetic markers and imaging QTs. We propose an efficient algorithm based on the alternative search method. Our method obtains better feature selection results than both regression and SCCA on both synthetic and real neuroimaging data. This demonstrates that our method is a promising bi-multivariate tool for brain imaging genetics.

Fast Multi-Task SCCA Learning with Feature Selection for Multi-Modal Brain Imaging Genetics.

Brain imaging genetics studies the genetic basis of brain structures and functions via integrating both genotypic data such as single nucleotide polymorphism (SNP) and imaging quantitative traits (QTs). In this area, both multi-task learning (MTL) and sparse canonical correlation analysis (SCCA) methods are widely used since they are superior to those independent and pairwise univariate analyses. MTL methods generally incorporate a few of QTs and are not designed for feature selection from a large number of QTs; while existing SCCA methods typically employ only one modality of QTs to study its association with SNPs. Both MTL and SCCA encounter computational challenges as the number of SNPs increases. In this paper, combining the merits of MTL and SCCA, we propose a novel multi-task SCCA (MTSCCA) learning framework to identify bi-multivariate associations between SNPs and multi-modal imaging QTs. MTSCCA could make use of the complementary information carried by different imaging modalities. Using the G 2,1-norm regularization, MTSCCA treats all SNPs in the same group together to enforce sparsity at the group level. The l 2 , 1 -norm penalty is used to jointly select features across multiple tasks for SNPs, and across multiple modalities for QTs. A fast optimization algorithm is proposed using the grouping information of SNPs. Compared with conventional SCCA methods, MTSCCA obtains improved performance regarding both correlation coefficients and canonical weights patterns. In addition, our method runs very fast and is easy-to-implement, and thus could provide a powerful tool for genome-wide brain-wide imaging genetic studies.

Brain imaging genetics in ADHD and beyond - Mapping pathways from gene to disorder at different levels of complexity.

Attention-deficit/hyperactivity disorder (ADHD) is a common and often persistent neurodevelopmental disorder. Beyond gene-finding, neurobiological parameters, such as brain structure, connectivity, and function, have been used to link genetic variation to ADHD symptomatology. We performed a systematic review of brain imaging genetics studies involving 62 ADHD candidate genes in childhood and adult ADHD cohorts. Fifty-one eligible research articles described studies of 13 ADHD candidate genes. Almost exclusively, single genetic variants were studied, mostly focussing on dopamine-related genes. While promising results have been reported, imaging genetics studies are thus far hampered by methodological differences in study design and analysis methodology, as well as limited sample sizes. Beyond reviewing imaging genetics studies, we also discuss the need for complementary approaches at multiple levels of biological complexity and emphasize the importance of combining and integrating findings across levels for a better understanding of biological pathways from gene to disease. These may include multi-modal imaging genetics studies, bioinformatic analyses, and functional analyses of cell and animal models.

Imaging genetics in neurodevelopmental psychopathology.

Neurodevelopmental disorders are defined by highly heritable problems during development and brain growth. Attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASDs), and intellectual disability (ID) are frequent neurodevelopmental disorders, with common comorbidity among them. Imaging genetics studies on the role of disease-linked genetic variants on brain structure and function have been performed to unravel the etiology of these disorders. Here, we reviewed imaging genetics literature on these disorders attempting to understand the mechanisms of individual disorders and their clinical overlap. For ADHD and ASD, we selected replicated candidate genes implicated through common genetic variants. For ID, which is mainly caused by rare variants, we included genes for relatively frequent forms of ID occurring comorbid with ADHD or ASD. We reviewed case-control studies and studies of risk variants in healthy individuals. Imaging genetics studies for ADHD were retrieved for SLC6A3/DAT1, DRD2, DRD4, NOS1, and SLC6A4/5HTT. For ASD, studies on CNTNAP2, MET, OXTR, and SLC6A4/5HTT were found. For ID, we reviewed the genes FMR1, TSC1 and TSC2, NF1, and MECP2. Alterations in brain volume, activity, and connectivity were observed. Several findings were consistent across studies, implicating, for example, SLC6A4/5HTT in brain activation and functional connectivity related to emotion regulation. However, many studies had small sample sizes, and hypothesis-based, brain region-specific studies were common. Results from available studies confirm that imaging genetics can provide insight into the link between genes, disease-related behavior, and the brain. However, the field is still in its early stages, and conclusions about shared mechanisms cannot yet be drawn.

Structured sparse CCA for brain imaging genetics via graph OSCAR.

BACKGROUND: Recently, structured sparse canonical correlation analysis (SCCA) has received increased attention in brain imaging genetics studies. It can identify bi-multivariate imaging genetic associations as well as select relevant features with desired structure information. These SCCA methods either use the fused lasso regularizer to induce the smoothness between ordered features, or use the signed pairwise difference which is dependent on the estimated sign of sample correlation. Besides, several other structured SCCA models use the group lasso or graph fused lasso to encourage group structure, but they require the structure/group information provided in advance which sometimes is not available. RESULTS: We propose a new structured SCCA model, which employs the graph OSCAR (GOSCAR) regularizer to encourage those highly correlated features to have similar or equal canonical weights. Our GOSCAR based SCCA has two advantages: 1) It does not require to pre-define the sign of the sample correlation, and thus could reduce the estimation bias. 2) It could pull those highly correlated features together no matter whether they are positively or negatively correlated. We evaluate our method using both synthetic data and real data. Using the 191 ROI measurements of amyloid imaging data, and 58 genetic markers within the APOE gene, our method identifies a strong association between APOE SNP rs429358 and the amyloid burden measure in the frontal region. In addition, the estimated canonical weights present a clear pattern which is preferable for further investigation. CONCLUSIONS: Our proposed method shows better or comparable performance on the synthetic data in terms of the estimated correlations and canonical loadings. It has successfully identified an important association between an Alzheimer's disease risk SNP rs429358 and the amyloid burden measure in the frontal region.

Sparse Canonical Correlation Analysis via Truncated ℓ1-norm with Application to Brain Imaging Genetics.

Discovering bi-multivariate associations between genetic markers and neuroimaging quantitative traits is a major task in brain imaging genetics. Sparse Canonical Correlation Analysis (SCCA) is a popular technique in this area for its powerful capability in identifying bi-multivariate relationships coupled with feature selection. The existing SCCA methods impose either the ℓ1-norm or its variants. The ℓ0-norm is more desirable, which however remains unexplored since the ℓ0-norm minimization is NP-hard. In this paper, we impose the truncated ℓ1-norm to improve the performance of the ℓ1-norm based SCCA methods. Besides, we propose two efficient optimization algorithms and prove their convergence. The experimental results, compared with two benchmark methods, show that our method identifies better and meaningful canonical loading patterns in both simulated and real imaging genetic analyse.

Converging evidence does not support GIT1 as an ADHD risk gene.

Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neuropsychiatric disorder with a complex genetic background. The G protein-coupled receptor kinase interacting ArfGAP 1 (GIT1) gene was previously associated with ADHD. We aimed at replicating the association of GIT1 with ADHD and investigated its role in cognitive and brain phenotypes. Gene-wide and single variant association analyses for GIT1 were performed for three cohorts: (1) the ADHD meta-analysis data set of the Psychiatric Genomics Consortium (PGC, N = 19,210), (2) the Dutch cohort of the International Multicentre persistent ADHD CollaboraTion (IMpACT-NL, N = 225), and (3) the Brain Imaging Genetics cohort (BIG, N = 1,300). Furthermore, functionality of the rs550818 variant as an expression quantitative trait locus (eQTL) for GIT1 was assessed in human blood samples. By using Drosophila melanogaster as a biological model system, we manipulated Git expression according to the outcome of the expression result and studied the effect of Git knockdown on neuronal morphology and locomotor activity. Association of rs550818 with ADHD was not confirmed, nor did a combination of variants in GIT1 show association with ADHD or any related measures in either of the investigated cohorts. However, the rs550818 risk-genotype did reduce GIT1 expression level. Git knockdown in Drosophila caused abnormal synapse and dendrite morphology, but did not affect locomotor activity. In summary, we could not confirm GIT1 as an ADHD candidate gene, while rs550818 was found to be an eQTL for GIT1. Despite GIT1's regulation of neuronal morphology, alterations in gene expression do not appear to have ADHD-related behavioral consequences. © 2015 Wiley Periodicals, Inc.