Bermudagrass (Cynodon spp.) breeding and cultivar development is hampered by limited information regarding its genetic and phenotypic diversity. A germplasm collection of 206 bermudagrass accessions from 29 countries was genotyped with high-throughput genotyping-by-sequencing technique. Genomic diversity in this diverse germplasm panel was assessed with multifaceted approaches including population structure, phylogenetic analysis, principal component analysis, and genetic diversity parameters. This study revealed substantial genetic variation in the Cynodon accessions, demonstrating the potential of this germplasm panel for further genetic studies and cultivar development in breeding programs. Another critical issue in turfgrass breeding is the lack of information regarding the genetic architecture of traits. Four agronomic traits leaf length, leaf width, internode distance and stem diameter were evaluated in a germplasm panel of common bermudagrass accessions. Then genome-wide association study was performed to dissect the genetic basis of the traits.

Flax (Linum usitatissimum L.) is a self-pollinated crop widely cultivated for fiber and oil production. Flaxseed is renowned for its health attributes but the presence of compounds, such as the heavy metal cadmium (Cd), is undesirable. Genomic studies in flax have produced large amounts of data in the last 15 years, providing useful resources to improve the genetic of this crop using genomics-based technologies and strategies. The goal of this thesis is therefore to capitalize on these advances to address the Cd problem and to propose solutions to improve breeding efficiencies. To find genomic-based solutions to Cd content, to the currently low breeding efficiency and to abiotic stress resistance in flax, this study utilized four major strategies: (1) genomic cross prediction, (2) gene family identification, (3) genome-wide association study (GWAS) and (4) genomic selection (GS). Characterization of the ATP-binding cassette (ABC) transporter and heavy metal associated (HMA) gene families was performed using the flax genome sequence. A total of 198 ABC transporter and 12 HMA genes were identified in the flax genome, of which nine were orthologous to Cd-associated genes in Arabidopsis, rice and maize. A transcriptomic analysis of eight tissues provided some support towards the functional annotation of these genes and confirmed the expression of these ABC transporter and HMA genes in flax seeds and other tissues. A diversity panel of 168 flax accessions was grown in the field at multiple locations and years and the seed content of 24 heavy metals (HMs) was measured. The panel was also sequenced and a single nucleotide polymorphism (SNP) dataset of nearly 43,000 SNPs was defined. A GWAS was conducted using these genotypic and phenotypic data and a total of 355 non-redundant quantitative trait nucleotides (QTNs) were identified for ten of the 24 metal contents. Overall, a total of 24 major and 331 minor effect QTNs were detected, including 11 that were pleiotropic. After allelic tests, 108 non-redundant QTNs were retained for eight of the ten metals and ranging from one for copper (Cu) to 70 for strontium (Sr). A total of 20 candidate genes for HM accumulation were identified at 12 of the 24 major QTN loci, of which five belonged to the ABC transporter family. Many of the metal contents, including Cd, appeared to be controlled by many genes of small effects; hence, GS is better suited than marker-assisted selection for application in breeding. To test this, predictive ability using ten GS statistical models was evaluated using trait-specific QTN and the random genome-wide 43K SNP datasets. Significantly higher predictive abilities were observed from the GS models built with the dataset made of QTNs associated with metal contents (70-80%) compared to that of the 43K dataset (10-25%). This study showed the feasibility of using GS to improve the predictive ability of polygenic traits such as metal content in seeds. GS can be applied in early generation selection to accelerate the improvement of abiotic stress resistance and either select low-Cd lines or discard high-Cd lines. These findings validate the use of a QTL-based strategy as a highly effective method for improving the efficiency of predictive ability of GS for highly complex traits such as resistance or tolerance to HM accumulation. Identification of both large and minor effect QTNs and/or pleiotropic effects hold potential for flax breeding improvement. Candidate gene functional validation can be performed using methods such as genome editing or targeting induced local lesions in genomes (TILLING).

No description available.

To leverage the extreme parallelism of emerging architectures, so that scientific applications can fulfill their high fidelity and multi-physics potential while sustaining high efficiency relative to the limiting resource, numerical algorithms must be redesigned. Algorithmic redesign is capable of shifting the limiting resource, for example from memory or communication to arithmetic capacity. The benefit of algorithmic redesign expands greatly when introducing a tunable tradeoff between accuracy and resources. Scientific applications from diverse sources rely on dense matrix operations. These operations arise in: Schur complements, integral equations, covariances in spatial statistics, ridge regression, radial basis functions from unstructured meshes, and kernel matrices from machine learning, among others. This thesis demonstrates how to extend the problem sizes that may be treated and to reduce their execution time. Two “universes” of algorithmic innovations have emerged to improve computations by orders of magnitude in capacity and runtime. Each introduces a hierarchy, of rank or precision. Tile Low-Rank approximation replaces blocks of dense operator with those of low rank. Mixed precision approximation, increasingly well supported by contemporary hardware, replaces blocks of high with low precision. Herein, we design new high-performance direct solvers based on the synergism of TLR and mixed precision. Since adapting to data sparsity leads to heterogeneous workloads, we rely on task-based runtime systems to orchestrate the scheduling of fine-grained kernels onto computational resources. We first demonstrate how TLR permits to accelerate acoustic scattering and mesh deformation simulations. Our solvers outperform the state-of-art libraries by up to an order of magnitude. Then, we demonstrate the impact of enabling mixed precision in bioinformatics context. Mixed precision enhances the performance up to three-fold speedup. To facilitate the adoption of task-based runtime systems, we introduce the AL4SAN library to provide a common API for the expression and queueing of tasks across multiple dynamic runtime systems. This library handles a variety of workloads at a low overhead, while increasing user productivity. AL4SAN enables interoperability by switching runtimes at runtime, which permits to achieve a twofold speedup on a task-based generalized symmetric eigenvalue solver.

Yes / Bone morphogenetic proteins (BMPs) play essential roles in the control of skin development, postnatal tissue remodelling and tumorigenesis. To explore whether some of the effects of BMP signalling are mediated by microRNAs, we performed genome-wide microRNA (miRNA) screening in primary mouse keratinocytes after BMP4 treatment. Microarray analysis revealed substantial BMP4-dependent changes in the expression of distinct miRNAs, including miR-21. Real-time PCR confirmed that BMP4 dramatically inhibits miR-21 expression in the keratinocytes. Consistently, significantly increased levels of miR-21 were observed in transgenic mice overexpressing the BMP antagonist noggin under control of the K14 promoter (K14-noggin). By in situ hybridization, miR-21 expression was observed in the epidermis and hair follicle epithelium in normal mouse skin. In K14-noggin skin, miR-21 was prominently expressed in the epidermis, as well as in the peripheral portion of trichofolliculoma-like hair follicle-derived tumours that contain proliferating and poorly differentiated cells. By transfecting keratinocytes with a miR-21 mimic, we identified the existence of two groups of the BMP target genes, which are differentially regulated by miR-21. These included selected BMP-dependent tumour-suppressor genes (Pten, Pdcd4, Timp3 and Tpm1) negatively regulated by miR-21, as well as miR-21-independent Id1, Id2, Id3 and Msx2 that predominantly mediate the effects of BMPs on cell differentiation. In primary keratinocytes and HaCaT cells, miR-21 prevented the inhibitory effects of BMP4 on cell proliferation and migration. Thus, our study establishes a novel mechanism for the regulation of BMP-induced effects in the skin and suggests miRNAs are important modulators of the effects of growth factor signalling pathways on skin development and tumorigenesis.

La scoliose idiopathique est une déformation tridimensionnelle de la colonne vertébrale dont la pathogenèse reste obscure. Cette maladie affecte 2-4% des adolescents de 10-18 ans parmi les garçons et les filles. Il est à noter que les filles sont plus sévèrement affectées et ce en plus grand nombre que les garçons. Les études de jumeaux ont montré que les facteurs génétiques jouent un rôle important dans la scoliose idiopathique de l'adolescent (SIA). Depuis 2010, les études d'association pan génomiques ont été multipliées dans les recherches, visant à trouver des gènes candidats impliqués dans la SIA à travers des examens des polymorphismes nucléotidiques (SNPs). Un test génétique nommé "ScoliScore" a été publié pour essayer de prédire la progression de courbure dans la population caucasienne. Cependant, l'association n'a pas été reproduite dans une grande étude japonaise, soulignant l'importance d'une étude de réplication dans une population caucasienne indépendante. Dans ce contexte, mon projet de maîtrise a permis de génotyper plus de 1,4 millions de SNPs dans une cohorte canadienne-française dans le but: 1) de valider l'association de ScoliScoreTM; et 2) d’identifier les variants génomiques associées à la SIA dans la population québécoise. Notre étude a montré qu’aucun des variants constituant le test ScoliScoreTM n’était associé à la SIA. Ceci suggère que l'absence d'association dans une cohorte japonaise n'est pas due à l'appartenance ethnique. Aussi, nous avons identifié des variants génomiques associés significativement à l’initiation et/ou la progression de SIA dans la population québécoise, suggérant des gènes candidats impliqués dans la pathogenèse de SIA. / Idiopathic scoliosis is a common spinal deformation occurring without clear reason. This disease affects 2-4% adolescents aging from 10-18 years old in both genders. Of note, girls are more affected in number and severity than boys. Twin studies demonstrated that genetic factors play an important role in adolescent idiopathic scoliosis (AIS). Since 2010, Genome-wide association studies (GWAS) have been multiplied in AIS researches, aiming to find out candidate genes involved in the disease by an examination of single nucleotide polymorphisms (SNPs) throughout the entire genome. A genetic test named “ScoliScore” was released for the prediction of curvature progression in Caucasian AIS population using 53 SNPs. However, such association was not replicated in a larger Japanese-population study. Such a discrepancy could be explained by ethnicity, raising the importance of a replication study in an independent Caucasian population of European descent. In that context, we genotyped over 1.4 million SNPs in a French-Canadian cohort: 1) to validate the association in ScoliScoreTM test; and 2) to identify genomic variants associated with AIS in the population of Quebec. As a result, the association of ScoliScoreTM genomic markers could not be reproduced in French-Canadian AIS patients, suggesting that the lack of association of these SNPs in a Japanese cohort is not due to ethnicity. Meanwhile, we identified genome-wide significant variants associated with spinal curve initiation and/or progression in French-Canadian population, suggesting candidate genes involved in AIS pathogenesis.

L'ulcère de Buruli (UB), infection à Mycobacterium ulcerans, troisième mycobactériose mondiale, connait une émergence rapide depuis 1980, essentiellement dans les pays d'Afrique subsaharienne. Jusqu’ici, les connaissances épidémiologiques sur l’UB étaient fondées sur des séries de cas cliniques non confirmés par laboratoire. Nous avons constitué la plus grande cohorte de cas confirmés à ce jour rassemblant plus de 1200 patients traités au CDTUB de Pobè au Bénin entre 2005 et 2011, afin de décrire l'épidémiologie clinique de la maladie et d'explorer l’architecture génétique de la susceptibilité à cette maladie. Les patients atteints d’UB sont des enfants (âge médian au diagnostic de 12 ans), présentant une lésion unique (96%), large (plus de 15 cm, 36%), ulcérative (66%) du membre inférieur (60%). Nous rapportons une présentation clinique atypique de l’UB, dans laquelle les patients présentent exclusivement une ostéomyélite à M. ulcerans. Le sex-ratio varie avec l’âge : les garçons sont majoritaires parmi les enfants (57% de patients masculins chez les moins de 15 ans), et les femmes parmi les adultes (33% de patients masculins). La présentation clinique dépend de l’âge et du sexe. 9% des patients masculins ont présenté une ostéomyélite contre 4% des patients féminins. Un an après la fin du traitement, 22% des patients présentent des séquelles fonctionnelles fixées. Une présentation clinique comportant une lésion oedémateuse, osseuse, de grande taille ou plusieurs lésions est significativement associée avec le développement de séquelles fonctionnelles (OR 7.64, IC95% [5.29-11.31]). Les patients coinfectés par le VIH ont un risque significativement plus élevé de développer un UB sévère (OR 2.77, IC95% [1.32-6.33]). Nous avons exploré l’architecture génétique de la susceptibilité à l’UB dans une perspective mendélienne et une perspective complexe. Le cas le plus sévère de la maladie observé dans ce centre appartient à une famille consanguine dans laquelle la ségrégation du phénotype suggère un défaut génétique mendélien récessif. Une analyse de liaison génétique par cartographie d'homozygotie suggère l’implication du locus des béta-défensines sur le chromosome 8 dans la pathogénèse de l'UB, et mène à l’identification d’une délétion homozygote ségrégeant parfaitement avec la maladie. Dans une perspective complexe, une étude d’association pangénomique a été réalisée après génotypage d’une cohorte de 400 cas et 400 témoins exposés sur plus de 2 millions de SNPs par la puce Illumina Omni2.5 et a permis l’identification de nombreux signaux d’intérêt. L’étude de réplication est en cours. La compréhension de la physiopathologie de l'infection à M. ulcerans est cruciale pour générer de nouvelles pistes thérapeutiques et vaccinales. La dissection du contrôle génétique de l'infection par l'hôte est en ce sens indispensable. / Buruli ulcer (BU), caused by Mycobacterium ulcerans, is the third most frequent mycobacteriosis worldwide. It has been rapidly emerging in sub-Saharan African countries since 1980. Until now, knowledge of BU epidemiology relied on series of non laboratory-confirmed clinical cases. From 2005-2011, we recruited the current largest cohort of laboratory-confirmed cases (more than 1,200 patients) at the Pobe CDTUB, Benin, to describe the clinical epidemiology of the disease and to explore the genetic architecture of human susceptibility to BU. Typically, patients with BU were children (median age at diagnosis 12 years) presenting with a unique (96%) large (≥15 cm, 36%) ulcerative (66%) lesion of the lower limb (60%). Atypical clinical presentation of BU included osteomyelitis with no identifiable present or past BU skin lesions. The sex ratio of BU widely varied with age, with male patients accounting for 57% of patients aged 15 years and younger, but only 33% of those older than 15 years. Clinical presentation of BU was significantly dependent on age and sex. 9% male patients had BU osteomyelitis, whereas only 4% of female patients did. 1 year after treatment, 22% of patients with follow-up information presented with permanent functional sequelae. Presentation with oedema, osteomyelitis, or large (≥15 cm in diameter), or multifocal lesions was significantly associated with occurrence of permanent functional sequelae (OR 7•64, 95% CI 5•29–11•31) and operationally defines severe BU. When coinfected with HIV, patients had a significantly higher risk to develop severe BU (OR 2.77, IC95% [1.32-6.33]). We explored the genetic architecture of susceptibility to BU in both mendelian and complex genetic frameworks. The most severe case of the disease to have been treated at the Pobe CDTUB belonged to a consanguineous family in which the segregation of the phenotype was indicative of a recessive mendelian genetic defect. Genetic linkage analysis by homozygosity mapping suggested the implication of the beta-defensin locus on chromosome 8 in BU pathogenesis and lead to the identification of a homozygous deletion, which co-segregated perfectly with the disease in the family. In a complex genetics approach, we undertook a genome-wide association study, which involved the genotyping of more than 2 million SNPs (Illumina Omni2.5) in a cohort of 400 cases and 400 exposed controls. We identified many signals of interest. The replication study is ongoing. Understanding BU physiopathology is crucial to the development of efficient vaccines and drugs. Dissection of the genetic control of the infection by M. ulcerans by its human host therefore constitutes an indispensable step.

Abstract Advances over the past few decades in ante- and neonatal care have led to the survival of a growing number of premature infants of extremely low gestational age. However, the occurrence of serious diseases, particularly those affecting the most immature infants, remains high. Bronchopulmonary dysplasia (BPD), a chronic lung disease of premature infants, is one such disease. Our current understanding of the molecular pathogenesis of BPD is incomplete; consequently, there are few preventive and therapeutic options for BPD. Moreover, it is challenging to predict the risk of BPD. Previous studies of BPD in twins revealed that the heritability of BPD is quite high. However, the individual genes that predispose premature infants to BPD are largely unknown. The aim of this study was to identify and study genes associated with BPD in order to investigate its pathogenesis. An additional aim was to add to knowledge of the risk of BPD in newborn premature infants, with an emphasis on twins. A candidate gene study found no consistent association between common polymorphisms of vascular endothelial growth factor receptor 2 and BPD. A second candidate gene study noted an association between the gene encoding Kit ligand and BPD. A genome-wide association study found a suggestive association between a locus close to the gene encoding C-reactive protein (CRP) and BPD, and in subsequent analyses, plasma levels of CRP during the first week of life predicted BPD. Finally, a nationwide register study found that the risk of BPD was lower in twins than in singletons. The results of this study add to what is known of the genetics and pathogenesis of BPD. They also provide new data on the risk of BPD, which may be used to improve early identification of infants for whom the risk of developing BPD is high. / Tiivistelmä Ennenaikaisen syntymän ja keskoslasten hoidon kehittymisen myötä yhä useammat huomattavan epäkypsinä syntyneet lapset jäävät henkiin. Samalla erityisesti juuri näitä lapsia uhkaavien sairauksien esiintyvyys on pysynyt korkeana. Bronkopulmonaalinen dysplasia (BPD, keskosen krooninen keuhkosairaus) on yksi näistä sairauksista. BPD:n molekyylitasoinen tautimekanismi on vielä osin tuntematon, eikä BPD:tä tehokkaasti estävää tai siitä parantavaa hoitoa ole. Myös BPD riskin arvioiminen vastasyntyneen keskoslapsen kohdalla on vaikeaa. BPD on huomattavan perinnöllinen tauti. BPD:lle altistavista geeneistä on kuitenkin vasta vähän tietoa. Tämän tutkimuksen tavoitteena oli lisätä tietoa BPD:n tautimekanismista tutkimalla BPD:lle altistavia geenejä. Lisäksi tutkimuksessa tarkasteltiin BPD:n esiintyvyyttä ja syntymää edeltäviä riskitekijöitä erityisesti kaksosten osalta. Ehdokasgeenitutkimuksessa verisuonten endoteelikasvutekijää koodaava geeni ei assosioitunut toistuvasti BPD:hen. Kit ligandia koodaava geeni sen sijaan assosioitui. Koko genomin assosiaatiotutkimuksessa C-reaktiivista proteiinia (CRP) koodaavan geenin lähistöltä löydettiin BPD:hen mahdollisesti assosioituva alue. Lisäksi ensimmäisen viikon CRP-arvojen osoitettiin ennakoivan myöhemmin kehittyvää BPD:tä. BPD-riskin todettiin olevan matalampi kaksi- kuin yksisikiöisistä raskauksista syntyneillä lapsilla. Tutkimuksen tulokset lisäävät tietoa BPD:n perinnöllisyydestä ja sitä kautta BPD:n tautimekanismista. Tutkimus toi myös uutta tietoa BPD:n riskitekijöistä parantaen vastasyntyneen keskoslapsen BPD-riskin arviota.

For more than half a decade, lithium has been successfully used to treat bipolar disorder. Worldwide, it is considered the first-line mood stabilizer. Apart from its proven antimanic and prophylactic effects, considerable evidence also suggests an antisuicidal effect in affective disorders. Lithium is also effectively used to augment antidepressant drugs in the treatment of refractory major depressive episodes and prevent relapses in recurrent unipolar depression. In contrast to many psychiatric drugs, lithium has outlasted various pharmacotherapeutic ‘fashions’, and remains an indispensable element in contemporary psychopharmacology. Nevertheless, data from pharmacogenetic studies of lithium are comparatively sparse, and these studies are generally characterized by small sample sizes and varying definitions of response. Here, we present an international effort to elucidate the genetic underpinnings of lithium response in bipolar disorder. Following an initiative by the International Group for the Study of Lithium-Treated Patients (www.IGSLI.org) and the Unit on the Genetic Basis of Mood and Anxiety Disorders at the National Institute of Mental Health,lithium researchers from around the world have formed the Consortium on Lithium Genetics (www.ConLiGen.org) to establish the largest sample to date for genome-wide studies of lithium response in bipolar disorder, currently comprising more than 1,200 patients characterized for response to lithium treatment. A stringent phenotype definition of response is one of the hallmarks of this collaboration. ConLiGen invites all lithium researchers to join its efforts. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Les recherches menées pour comprendre les troubles du spectre autistique (TSA) et la schizophrénie (SZ) ont communément utilisé une approche dite descendante, partant du diagnostic clinique pour investiguer des phénotypes intermédiaires cérébraux ainsi que des variations génétiques associées. Des études transdiagnostiques récentes ont remis en question ces frontières nosologiques, et suggèrent des mécanismes étiologiques imbriqués. L’approche montante propose de composer des groupes de porteurs d’un même variant génétique afin d’investiguer leur contribution aux conditions neuropsychiatriques (NPs) associées. Les variations du nombre de copies (CNV, perte ou gain d’un fragment d’ADN) figurent parmi les facteurs biologiques les plus associés aux NPs, et sont dès lors des candidats particulièrement appropriés. Les CNVs induisant un risque pour des conditions similaires, nous posons l’hypothèse que des classes entières de CNVs convergent sur des dimensions d’altérations cérébrales qui contribuent aux NPs. L’imagerie fonctionnelle au repos (rs-fMRI) s’est révélée un outil prometteur en psychiatrie, mais presqu’aucune étude n’a été menée pour comprendre l’impact des CNVs sur la connectivité fonctionnelle cérébrale (FC). Nos objectifs étaient de: 1) Caractériser l’effet des CNVs sur la FC; 2) Rechercher la présence des motifs conférés par ces signatures biologiques dans des conditions idiopathiques; 3) Tester si la suppression de gènes intolérants à l’haploinsuffisance réorganise la FC de manière indépendante à leur localisation dans le génome. Nous avons agrégé des données de rs-fMRI chez: 502 porteurs de 8 CNVs associées aux NPs (CNVs-NP), de 4 CNVs sans association établie, ainsi que de porteurs de CNVs-NPs éparses; 756 sujets ayant un diagnostic de TSA, de SZ, ou de trouble déficitaire de l’attention/hyperactivité (TDAH), et 5377 contrôles. Les analyses du connectome entier ont montré un effet de dosage génique positif pour les CNVs 22q11.2 et 1q21.1, et négatif pour le 16p11.2. La taille de l’effet des CNVs sur la FC était corrélée au niveau de risque psychiatrique conféré par le CNV. En accord avec leurs effets sur la cognition, l’effet des délétions sur la FC était plus élevé que celui des duplications. Nous avons identifié des similarités entre les motifs cérébraux conférés par les CNVs-NP, et l’architecture fonctionnelle des individus avec NPs. Le niveau de similarité était associé à la sévérité du CNV, et était plus fort avec la SZ et les TSA qu’avec les TDAH. La comparaison des motifs conférés par les délétions les plus sévères (16p11.2, 22q11.2) à l’échelle fonctionnelle, et d’expression génique, nous a confirmé l’existence présumée de relation entre les mutations elles-mêmes. À l’aide d’une mesure d’intolérance aux mutations (pLI), nous avons pu inclure tous les porteurs de CNVs disponibles, et ainsi identifier un profil d’haploinsuffisance impliquant le thalamus, le cortex antérieur cingulaire, et le réseau somato-moteur, associé à une diminution de mesure d’intelligence générale. Enfin, une analyse d’exploration factorielle nous a permis de confirmer la contribution de ces régions cérébrales à 3 composantes latentes partagées entre les CNVs et les NPs. Nos résultats ouvrent de nouvelles perspectives dans la compréhension des mécanismes polygéniques à l’oeuvre dans les maladies mentales, ainsi que des effets pléiotropiques des CNVs. / Research on Autism Spectrum Disorder (ASD) and schizophrenia (SZ) has mainly adopted a ‘top-down’ approach, starting from psychiatric diagnosis, and moving to intermediate brain phenotypes and underlying genetic factors. Recent cross-disorder studies have raised questions about diagnostic boundaries and pleiotropic mechanisms. By contrast, the recruitment of groups based on the presence of a genetic risk factor allows for the investigation of molecular pathways related to a particular risk for neuropsychiatric conditions (NPs). Copy number variants (CNVs, loss or gain of a DNA segment), which confer high risk for NPs are natural candidates to conduct such bottom-up approaches. Because CNVs have a similar range of adverse effects on NPs, we hypothesized that entire classes of CNVs may converge upon shared connectivity dimensions contributing to mental illness. Resting-state functional MRI (rs-fMRI) studies have provided critical insight into the architecture of brain networks involved in NPs, but so far only a few studies have investigated networks modulated by CNVs. We aimed at 1) Delineating the effects of neuropsychiatric variants on functional connectivity (FC), 2) Investigating whether the alterations associated with CNVs are also found among idiopathic psychiatric populations, 3) Testing whether deletions reorganize FC along general dimensions, irrespective of their localization in the genome. We gathered rsfMRI data on 502 carriers of eight NP-CNVs (high-risk), four CNVs without prior association to NPs as well as carriers of eight scarcer NP-CNVs. We also analyzed 756 subjects with idiopathic ASD, SZ, and attention deficit hyperactivity disorder (ADHD), and 5,377 controls. Connectome-wide analyses showed a positive gene dosage effect for the 22q11.2 and 1q21.1 CNVs, and a negative association for the 16p11.2 CNV. The effect size of CNVs on relative FC (mean-connectivity adjusted) was correlated with the known level of NP-risk conferred by CNVs. Consistent with results on cognition, we also reported that deletions had a larger effect size on FC than duplications. We identified similarities between high-risk CNV profiles and the connectivity architecture of individuals with NPs. The level of similarity was associated with mutation severity and was strongest in SZ, followed by ASD, and ADHD. The similarity was driven by the thalamus, and the posterior cingulate cortex, previously identified as hubs in transdiagnostic psychiatric studies. These results raised questions about shared mechanisms across CNVs. By comparing deletions at the 16p11.2 and 22q11.2 loci, we identified similarities at the connectivity, and at the gene expression level. We extended this work by pooling all deletions available for analysis. We asked if connectivity alterations were associated with the severity of deletions scored using pLI, a measure of intolerance to haploinsufficiency. The haploinsufficiency profile involved the thalamus, anterior cingulate cortex, and somatomotor network and was correlated with lower general intelligence and higher autism severity scores in 3 unselected and disease cohorts. An exploratory factor analysis confirmed the contribution of these regions to three latent components shared across CNVs and NPs. Our results open new avenues for understanding polygenicity in psychiatric conditions, and the pleiotropic effect of CNVs on cognition and on risk for neuropsychiatric disorders.