Marzia was interviewed about her newsworthy OHBM 2017 contribution!! Click here to read the interview!
Our paper with the title “Overdominant effect of a CHRNA4 polymorphism on cingulo-opercular network activity and cognitive control” is now available online at the Journal of Neuroscience.
The nicotinic system plays an important role in cognitive control, and is implicated in several neuropsychiatric conditions. Yet, the contributions of genetic variability in this system to individuals’ cognitive control abilities are poorly understood, and the brain processes that mediate such genetic contributions remain largely unidentified. In this first large-scale neuroimaging genetics study of the human nicotinic receptor system (two cohorts, males and females, fMRI total N=1586, behavioral total N=3650), we investigated a common polymorphism of the high-affinity nicotinic receptor α4β2 (rs1044396 on the CHRNA4 gene) previously implicated in behavioral and nicotine-related studies (albeit with inconsistent major/minor allele impacts). Based on our prior neuroimaging findings, we expected this polymorphism to impact neural activity in the cingulo-opercular network involved in core cognitive control processes including maintenance of alertness. Consistent across the cohorts, all cortical areas of the cingulo-opercular network showed higher activity in heterozygotes compared to both types of homozygotes during cognitive engagement. This inverted U-shaped relation reflects an overdominant effect, i.e. allelic interaction (cumulative evidence p=1.33*10-5). Furthermore, heterozygotes performed more accurately in behavioral tasks that primarily depend on sustained alertness. No effects were observed for haplotypes of the surrounding CHRNA4 region, supporting a true overdominant effect at rs1044396. As a possible mechanism, we observed that this polymorphism is an expression quantitative trait locus (eQTL) modulating CHRNA4 expression levels. This is the first report of overdominance in the nicotinic system. These findings connect CHRNA4 genotype, cingulo-opercular network activation and sustained alertness, providing insights into how genetics shapes individuals’ cognitive control abilities.
The nicotinic acetylcholine system plays a central role in neuromodulatory regulation of cognitive control processes, and is dysregulated in several neuropsychiatric disorders. In spite of this functional importance, no large-scale neuroimaging genetics studies have targeted the contributions of genetic variability in this system to human brain activity. Here, we show impact of a common polymorphism of the high-affinity nicotinic receptor α4β2, consistent across brain activity and behavior in two large human cohorts. We report a hitherto unknown overdominant effect (allelic interaction) at this locus, where the heterozygotes show higher activity in the cingulo-opercular network underlying alertness maintenance, and higher behavioral alertness performance than both homozygous groups. This gene-brain-behavior relationship informs about the biological basis of inter-individual differences in cognitive control.
Our paper with the title “Overdominant effect of a CHRNA4 polymorphism on cingulo-opercular network activity and cognitive control” was accepted for publication in the Journal of Neuroscience.
Authors: Sepideh Sadaghiani, Bernard Ng, Andre Altmann, Jean-Baptiste Poline, Tobias Banaschewski, Arun Bokde, Uli Bromberg, Christian Büchel, Erin Burke Quinlan, Patricia Conrod, Sylvane Desrivières, Herta Flor, Vincent Frouin, Hugh Garavan, Penny Gowland, Juergen Gallinat, Andreas Heinz, Bernd Ittermann, Jean-Luc Martinot, Marie-Laure Martinot, Hervé Lemaitre, Frauke Nees, Dimitri Papadopoulos Orfanos, Tomas Paus, Luise Poustka, Sabina Millenet, Juliane Fröhner, Michael Smolka, Henrik Walter, Robert Whelan, Gunter Schumann, Valerio Napolioni, Michael Greicius
Our abstract “Multimodal Imaging Disease Progression Scores as Quantitative Traits in GWAS of the ADNI Cohort” was selected for an oral presentation at OHBM 2017, Vancouver, Canada!
On top of that lead author Marzia Scelsi received a Merit Abstract Award for the 2017 OHBM Annual Meeting. Congrats Marzia!
M. A. Scelsi, M. Lorenzi, J. M. Schott, S. Ourselin, A. Altmann, “Multimodal Imaging Disease Progression Scores as Quantitative Traits in GWAS of the ADNI Cohort”
Quantitative trait genome-wide association studies (GWAS) in late-onset Alzheimer’s disease (AD) using imaging biomarkers focused either on cross-sectional or on longitudinal phenotypes derived from a single imaging modality. However, since clinical and imaging biomarkers in AD are highly interrelated, association studies based on single biomarkers may miss genetic factors influencing their joint variation. In order to account for their joint variability, in this work we propose to use two well-established AD biomarkers to define a disease progression score (DPS), and to subsequently perform a GWAS using this DPS as a novel quantitative phenotype.
Our work on distributed partial least squares (PLS) has been accepted for an oral presentation at SIPAIM 2016. An earlier version of this paper was presented by Marco Lorenzi at MASAMB (Matematical and Statistical aspects of Molecular Biology) in Cambridge in early October.
Title: Secure multivariate large-scale multi-centric analysis through on-line learning: an imaging genetics case study
Authors: Marco Lorenzi, Boris Gutman, Paul M. Thompson, Daniel C. Alexander, Sebastien Ourselin, Andre Altmann
Abstract: State-of-the-art data analysis methods in genetics and related fields have advanced beyond massively univariate analyses. However, these methods suffer from the limited amount of data available at a single research site. Re- cent large-scale multi-centric imaging-genetic studies, such as ENIGMA, have to rely on meta-analysis of mass univariate models to achieve critical sample sizes for uncovering statistically significant associations. Indeed, model parameters, but not data, can be securely and anonymously shared between partners. We propose here partial least squares (PLS) as a multivariate imaging-genetics model in meta-studies. In particular, we propose an online estimation approach to partial least squares for the sequential estimation of the model parameters in data batches, based on an approximation of the singular value decomposition (SVD) of partitioned covariance matrices. We applied the proposed approach to the challenging problem of modeling the association between 1,167,117 genetic markers (SNPs, single nucleotide polymorphisms) and the brain cortical and sub-cortical atrophy (354,804 anatomical surface features) in a cohort of 639 individuals from the Alzheimer’s Disease Neuroimaging Initiative. We compared two different modeling strategies (sequential- and meta-PLS) to the classic non-distributed PLS. Both strategies exhibited only minimal approximation errors of model parameters. The proposed approaches pave the way to the application of multivariate models in large scale imaging-genetics meta-studies, and may lead to novel understandings of the complex brain phenotype-genotype interactions.
Two of our contributions to the recent AAIC in Toronto have been highlighted in an Alzforum news item. Click here to read the article.
We just added the Re-Annotator annotation for the custom microarray chip from Agilent used by the Allen Institute for Brain Sciences. Get the annotation here. This annotation was also used for our recent paper in Science. We are also taking requests for frequently used chips to be added to the page, just email us! If you use Re-Annotator or the resulting annotations, please cite our paper.
Our paper with the title “Partial Least Squares Modeling for Imaging-Genetics in Alzheimer’s Disease: Plausibility and Generalization” was accepted for presentation at ISBI 2016.
Two of our recent works were highlighted!
Our paper entitled “Sex modifies APOE-related risk of developing Alzheimer’s Disease” was highlighted in “Recognizing the problem of delayed entry in time-to-event studies: Better late than never for clinical neuroscientists” for its proper use of survival analysis.
Further, our paper entitled “Regional Brain Hypometabolism Is Unrelated to Regional Amyloid Plaque Burden” received a scientific comment by Sorg and Grothe within the same issue with the title “The complex link between amyloid and neuronal dysfunction in Alzheimer’s disease“.