Jakub Kopal

Worrawat Engchuan

Thomas Renne

Martineau Jean-Louis

Omar Shanta

Zohra Saci

Bhooma Thiruvahindrapuram

Jeffrey MacDonald

Josephine Mollon

Laura M Schultz

Emma E M Knowles

David Porteous

Gail Davies

Paul Redmond

Sarah Harris

Simon Cox

Gunter Schumann … (see 9 more)

Zdenka Pausova

Celia Greenwood

Tomas Paus

Stephen Scherer

Laura Almasy

Jonathan Sebat

David Glahn

Sébastien Jacquemont

Cognitive deficits are common across many neurodevelopmental and psychiatric conditions, including those studied in the current set of PGC-C… (see more)NV papers. How changes in regional gene expression across the cerebral cortex influence cognitive ability remains unknown. Population variation in gene dosage—which significantly impacts gene expression—represents a unique paradigm to address this question. We developed a cerebral-cortex gene-set burden analysis (CC-GSBA) to associate a trait with genomic deletions and duplications that disrupt genes with similar expression profiles across 180 cortical regions. We performed CC-GSBA across 180 cortical regions to test associations with cognitive ability in 260,000 individuals from general population cohorts. Most cortical gene sets were associated with a decrease in cognitive ability when deleted or duplicated, and this novel approach revealed opposing cortical patterns for the effect sizes of deletions and duplications. These cortical patterns of effect sizes followed the cortical gradient previously characterized at the molecular, cellular, and functional levels. We show that genes with preferential expression in sensorimotor regions demonstrated the largest effect on cognition when deleted. At the opposing end of the cortical gradient, genes with preferential expression in multimodal association regions affected cognition the most when duplicated. These two gene dosage cortical patterns could not be explained by particular cell types, developmental epochs, or genetic constraints, highlighting the fact that the macroscopic network organization of the cerebral cortex is key to understanding the effects of gene dosage on cognitive traits.

2025-11-27

Research Square (preprint)

Cortical differences across psychiatric disorders and associated common and rare genetic variants

Kuldeep Kumar

Zhijie Liao

Clara Moreau

Christopher R. K. Ching

Claudia Modenato

Will Snyder

Sayeh Kazem

Charles-Olivier Martin

C.O. Martin

Anne-Marie Bélanger

Valérie K. Fontaine

Khadije Jizi

Rune Boen

Zohra Saci

Leila Kushan

Ana I. Silva

Marianne B.M. van den Bree

David E.J. Linden … (see 16 more)

Michael J. Owen

Jeremy Hall

Sarah Lippé

Bogdan Draganski

Laura Almasy

Sophia I. Thomopoulos

Neda Jahanshad

Ida E. Sønderby

Ole A. Andreassen

David C. Glahn

Armin Raznahan

Carrie Bearden

Tomas Paus

Paul M. Thompson

Sébastien Jacquemont

2025-04-19

medRxiv (preprint)

Mirror effect of genomic deletions and duplications on cognitive ability across the human cerebral cortex

Kuldeep Kumar

Sayeh Kazem

Thomas Renne

Worrawat Engchuan

Martineau Jean-Louis

Zohra Saci

Omar Shanta

Bhooma Thiruvahindrapuram

Jeffrey R. MacDonald

Josephine Mollon

Laura Schultz

Emma E M Knowles

David Porteous

Gail Davies

Paul Redmond

Sarah E. Harris

Simon R. Cox

Gunter Schumann … (see 9 more)

Zdenka Pausova

Celia M. T. Greenwood

Tomas Paus

Stephen W Scherer

Laura Almasy

Jonathan Sebat

David C. Glahn

Sébastien Jacquemont

Regulation of gene expression shapes the interaction between brain networks which in-turn supports psychological processes such as cognitive… (see more) ability. How changes in level of gene expression across the cerebral cortex influence cognitive ability remains unknown. Here, we tackle this by leveraging genomic deletions and duplications - copy number variants (CNVs) that fully encompass one or more genes expressed in the human cortex - which lead to large effects on gene-expression levels. We assigned genes to 180 regions of the human cerebral cortex based on their preferential expression across the cortex computed using data from the Allen Human Brain Atlas. We aggregated CNVs in cortical regions, and ran a burden association analysis to compute the mean effect size of genes on general cognitive ability for each of the 180 regions. When affected by CNVs, most of the regional gene-sets were associated with lower cognitive ability. The spatial patterns of effect sizes across the cortex were correlated negatively between deletions and duplications. The largest effect sizes for deletions and duplications were observed for gene-sets with high expression in sensorimotor and association regions, respectively. These two opposing patterns of effect sizes were not influenced by intolerance to loss of function, demonstrating orthogonality to dosage-sensitivity scores. The same mirror patterns were also observed after stratifying genes based on cell types and developmental epochs markers. These results suggest that the effect size of gene dosage on cognitive ability follows a cortical gradient. The same brain region and corresponding gene-set may show different effects on cognition depending on whether variants increase or decrease transcription. The latter has major implications for the association of brain networks with phenotypes

2025-01-07

bioRxiv (preprint)

Mirror effect of genomic deletions and duplications on cognitive ability across the human cerebral cortex

Kuldeep Kumar

Sayeh Kazem

Thomas Renne

Worrawat Engchuan

Martineau Jean-Louis

Zohra Saci

Omar Shanta

Bhooma Thiruvahindrapuram

Jeffrey R. MacDonald

Josephine Mollon

Laura Schultz

Emma E M Knowles

David Porteous

Gail Davies

Paul Redmond

Sarah E. Harris

Simon R. Cox

Gunter Schumann … (see 9 more)

Zdenka Pausova

Celia M. T. Greenwood

Tomas Paus

Stephen W Scherer

Laura Almasy

Jonathan Sebat

David C. Glahn

Sébastien Jacquemont

Regulation of gene expression shapes the interaction between brain networks which in-turn supports psychological processes such as cognitive… (see more) ability. How changes in level of gene expression across the cerebral cortex influence cognitive ability remains unknown. Here, we tackle this by leveraging genomic deletions and duplications - copy number variants (CNVs) that fully encompass one or more genes expressed in the human cortex - which lead to large effects on gene-expression levels. We assigned genes to 180 regions of the human cerebral cortex based on their preferential expression across the cortex computed using data from the Allen Human Brain Atlas. We aggregated CNVs in cortical regions, and ran a burden association analysis to compute the mean effect size of genes on general cognitive ability for each of the 180 regions. When affected by CNVs, most of the regional gene-sets were associated with lower cognitive ability. The spatial patterns of effect sizes across the cortex were correlated negatively between deletions and duplications. The largest effect sizes for deletions and duplications were observed for gene-sets with high expression in sensorimotor and association regions, respectively. These two opposing patterns of effect sizes were not influenced by intolerance to loss of function, demonstrating orthogonality to dosage-sensitivity scores. The same mirror patterns were also observed after stratifying genes based on cell types and developmental epochs markers. These results suggest that the effect size of gene dosage on cognitive ability follows a cortical gradient. The same brain region and corresponding gene-set may show different effects on cognition depending on whether variants increase or decrease transcription. The latter has major implications for the association of brain networks with phenotypes

2025-01-07

bioRxiv (preprint)

295. Rare Variant Genetic Architecture of the Human Cortical MRI Phenotypes in General Population

Kuldeep Kumar

Sayeh Kazem

Zhijie Liao

Thomas Renne

Martineau Jean-Louis

Zhe Xie

Zohra Saci

Laura Almasy

David C. Glahn

Tomas Paus

Carrie Bearden

Paul Thompson

Richard A.I. Bethlehem

Varun Warrier

Sébastien Jacquemont

2024-05-01

Biological Psychiatry (published)

F66. FROM GENE TO COGNITION: MAPPING THE EFFECTS OF GENOMIC DELETIONS AND DUPLICATIONS ON COGNITIVE ABILITY

Sayeh Kazem

Kuldeep Kumar

Thomas Renne

Martineau Jean-Louis

Zohra Saci

Laura Almasy

David C. Glahn

Guy Wolf

Sébastien Jacquemont

2023-10-01

European Neuropsychopharmacology (published)

Bayesian modeling disentangles language versus executive control disruption in stroke

Gesa Hartwigsen

Jae‐Sung Lim

Hee-Joon Bae

Kyung‐Ho Yu

Hugo J. Kuijf

Nick A. Weaver

J. Matthijs Biesbroek

2023-08-07

bioRxiv (preprint)

The default network dominates neural responses to evolving movie stories

Enning Yang

Filip Milisav

Avram J. Holmes

Georgios D. Mitsis

Bratislav Mišić

Emily S. Finn

2023-07-14

Nature Communications (published)

Using rare genetic mutations to revisit structural brain asymmetry

Kuldeep Kumar

Kimia Shafighi

Karin Saltoun

Claudia Modenato

Clara A. Moreau

Martineau Jean-Louis

Charles-Olivier Martin

C.O. Martin

Zohra Saci

Nadine Younis

Elise Douard

Khadije Jizi

Alexis Beauchamp-Chatel

Leila Kushan

Ana I. Silva

Marianne B.M. van den Bree

David E.J. Linden

M. J. Owen … (see 11 more)

Jeremy Hall

Sarah Lippé

Bogdan Draganski

Ida E. Sønderby

Ole A. Andreassen

David C. Glahn

Paul M. Thompson

Carrie E. Bearden

Robert Zatorre

Sébastien Jacquemont

2023-04-18

bioRxiv (preprint)

The end game: respecting major sources of population diversity

Lucina Q. Uddin

2023-03-03

Nature Methods (published)

Rare CNVs and phenome-wide profiling highlight brain structural divergence and phenotypical convergence

Kuldeep Kumar

Karin Saltoun

Claudia Modenato

Clara A. Moreau

Sandra Martin-Brevet

Martineau Jean-Louis

Charles-Olivier Martin

C.O. Martin

Zohra Saci

Nadine Younis

Petra Tamer

Elise Douard

Anne M. Maillard

Borja Rodriguez-Herreros

Aurélie Pain

Sonia Richetin

Leila Kushan

Ana I. Silva … (see 13 more)

Marianne B.M. van den Bree

David E.J. Linden

M. J. Owen

Jeremy Hall

Sarah Lippé

Bogdan Draganski

Ida E. Sønderby

Ole A. Andreassen

David C. Glahn

Paul M. Thompson

Carrie E. Bearden

Sébastien Jacquemont

2023-03-02

Nature human behaviour (published)

Endorsing Complexity Through Diversity: Computational Psychiatry Meets Big Data Analytics

2022-08-01

Biological Psychiatry (published)