Jakub Kopal

Carriers of LRRK2 pathogenic variants show a milder, anatomically distinct brain signature of Parkinson's disease

Andrew Vo

Qin Tao

Tanya Simuni

Lana M. Chahine

Alain Dagher

Pathogenic LRRK2 gene variants are a major genetic risk factor for both familial and sporadic Pa… (see more)rkinson’s dissease (PD), opening an unattended window into disease mechanisms and potential therapies. Investigating the influence of pathogenic variants in LRRK2 gene on brain structure is a crucial step toward enabling early diagnosis and personalized treatment. Yet, despite its significance, the ways in which LRRK2 genotype affects brain structure remain largely unexplored. Work in this domain is plagued by small sample sizes and differences in cohort composition, which can obscure genuine distinctions among clinical subgroups. In this study, we overcome such important limitations by combining explicit modeling of population background variation and pattern matching. Specifically, we leverage a cohort of 603 participants (including 370 with a PD diagnosis) to examine MRI-detectable cortical atrophy patterns associated with the LRRK2 pathogenic variants in people with PD and carriers without Parkinson’s symptoms. LRRK2 PD patients exhibit milder cortical thinning compared to sporadic PD, with notable preservation in temporal and occipital regions, suggesting a distinct pattern of neurodegeneration. Non-manifesting LRRK2 carriers show no significant cortical atrophy, indicating no structural signs of subclinical PD. We further analyze the relationship between aggregated alpha-synuclein in cerebrospinal fluid and atrophy. We find that those with evidence of aggregated alpha-synuclein experienced pronounced neurodegeneration and increased cortical thinning, possibly defining another aggressive PD subtype. Our findings highlight genetic avenues for distinguishing PD subtypes, which could lead to more targeted treatment approaches and a more complete understanding of Parkinson’s disease progression.

2026-01-02

Communications Medicine (published)

doi.org

Latent brain subtypes of chronotype reveal unique behavioral and health profiles across population cohorts

Julie Carrier

Kai-Florian Storch

Robin I. M. Dunbar

Danilo Bzdok

Chronotype is shaped by the complex interplay of endogenous and exogenous factors. This time-enduring trait ties into societal behaviors an… (see more)d is linked to psychiatric and metabolic conditions. Despite its multifaceted nature, prior research has treated chronotype as a monolithic trait across the population, risking overlooking substantial heterogeneity in neural and behavioral fingerprints. To uncover hidden subgroups, we develop a supervised pattern-learning framework integrating three complementary brain-imaging modalities with deep behavioral and health profiling from 27,030 UK Biobank participants. We identify five distinct, biologically valid chronotype subtypes. Each demonstrates unique patterns across brain, behavioral and health profiles. External validation in 10,550 US children from the ABCD Study cohort reveals reversed age distributions and replicates sex-associated brain-behavioral patterns, suggesting that potential divergences between chronotype traits observed throughout adulthood may begin to emerge early in life. These findings highlight underappreciated sources of population variation that echo the rhythm of people’s inner clock.

2025-12-21

Nature Communications (published)

doi.org

Latent brain subtypes of chronotype reveal unique behavioral and health profiles across population cohorts

Julie Carrier

Kai-Florian Storch

Robin I. M. Dunbar

Danilo Bzdok

Chronotype is shaped by the complex interplay of endogenous and exogenous factors. This time-enduring trait ties into societal behaviors an… (see more)d is linked to psychiatric and metabolic conditions. Despite its multifaceted nature, prior research has treated chronotype as a monolithic trait across the population, risking overlooking substantial heterogeneity in neural and behavioral fingerprints. To uncover hidden subgroups, we develop a supervised pattern-learning framework integrating three complementary brain-imaging modalities with deep behavioral and health profiling from 27,030 UK Biobank participants. We identify five distinct, biologically valid chronotype subtypes. Each demonstrates unique patterns across brain, behavioral and health profiles. External validation in 10,550 US children from the ABCD Study cohort reveals reversed age distributions and replicates sex-associated brain-behavioral patterns, suggesting that potential divergences between chronotype traits observed throughout adulthood may begin to emerge early in life. These findings highlight underappreciated sources of population variation that echo the rhythm of people’s inner clock.

2025-12-21

Nature Communications (published)

doi.org

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

Kuldeep Kumar

Sayeh Kazem

Guillaume Huguet

Worrawat Engchuan

Jakub Kopal

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

Tomáš Paus

Stephen Scherer

Laura Almasy

Jonathan Sebat

David Glahn

Guillaume Dumas

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)

doi.org

Deep learning reveals that multidimensional social status drives population variation in 11,875 US participant cohort

Avram J. Holmes

Sarah W. Yip

Danilo Bzdok

As an increasing realization, many behavioral relationships are interwoven with inherent variations in human populations. Presently, there i… (see more)s no clarity in the biomedical community on which sources of population variation are most dominant. The recent advent of population-scale cohorts like the Adolescent Brain Cognitive DevelopmentSM Study (ABCD Study®) are now offering unprecedented depth and width of phenotype profiling that potentially explains interfamily differences. Here, we leveraged a deep learning framework (conditional variational autoencoder) on the totality of the ABCD Study® phenome (8,902 candidate phenotypes in 11,875 participants) to identify and characterize major sources of population stratification. 80% of the top 5 sources of explanatory stratifications were driven by distinct combinations of 202 available socioeconomic status (SES) measures; each in conjunction with a unique set of non-overlapping social and environmental factors. Several sources of variation across this cohort flagged geographies marked by material poverty interlocked with mental health and behavioral correlates. Deprivation emerged in another top stratification in relation to urbanicity and its ties to immigrant and racial and ethnic minoritized groups. Conversely, two other major sources of population variation were both driven by indicators of privilege: one highlighted measures of access to educational opportunity and income tied to healthy home environments and good behavior, the other profiled individuals of European ancestry leading advantaged lifestyles in desirable neighborhoods in terms of location and air quality. Overall, the disclosed social stratifications underscore the importance of treating SES as a multidimensional construct and recognizing its ties into social determinants of health.

2025-08-12

PLOS One (published)

doi.org

Deep learning reveals that multidimensional social status drives population variation in 11,875 US participant cohort

Avram J. Holmes

Sarah W. Yip

Danilo Bzdok

As an increasing realization, many behavioral relationships are interwoven with inherent variations in human populations. Presently, there i… (see more)s no clarity in the biomedical community on which sources of population variation are most dominant. The recent advent of population-scale cohorts like the Adolescent Brain Cognitive DevelopmentSM Study (ABCD Study®) are now offering unprecedented depth and width of phenotype profiling that potentially explains interfamily differences. Here, we leveraged a deep learning framework (conditional variational autoencoder) on the totality of the ABCD Study® phenome (8,902 candidate phenotypes in 11,875 participants) to identify and characterize major sources of population stratification. 80% of the top 5 sources of explanatory stratifications were driven by distinct combinations of 202 available socioeconomic status (SES) measures; each in conjunction with a unique set of non-overlapping social and environmental factors. Several sources of variation across this cohort flagged geographies marked by material poverty interlocked with mental health and behavioral correlates. Deprivation emerged in another top stratification in relation to urbanicity and its ties to immigrant and racial and ethnic minoritized groups. Conversely, two other major sources of population variation were both driven by indicators of privilege: one highlighted measures of access to educational opportunity and income tied to healthy home environments and good behavior, the other profiled individuals of European ancestry leading advantaged lifestyles in desirable neighborhoods in terms of location and air quality. Overall, the disclosed social stratifications underscore the importance of treating SES as a multidimensional construct and recognizing its ties into social determinants of health.

2025-08-12

Public Library of Science ONE (published)

doi.org

Latent brain subtypes of chronotype reveal unique behavioral and health profiles: an across-cohort validation

Julie Carrier

Kai-Florian Storch

Robin Dunbar

Danilo Bzdok

Chronotype is shaped by the complex interplay of endogenous and exogenous factors. This trait ties into various behaviors in the wider socie… (see more)ty and is linked to the prevalence of psychiatric and metabolic conditions. Despite its multifaceted nature, prior research has treated chronotype as a monolithic trait across the population, risking overlooking substantial heterogeneity in neural and behavioral fingerprints of both early risers and night owls. To test for such hidden subgroups, we developed a supervised pattern-learning framework for trait subtyping, integrating three complementary brain-imaging modalities with deep behavior, diagnosis, and drug prescription profiling from 27,030 UK Biobank participants. We identified and characterized five distinct biologically valid chronotype subtypes: (1) typical eveningness, (2) depression-associated eveningness, (3) typical morningness, (4) morningness with greater expression in females, and (5) eveningness with greater expression in males. Each uncovered subtype showed unique patterns across brain, behavioral and health profiles. We finally externally validated these subtypes in 10,550 US children from the ABCD Study® cohort, which revealed reversed age distributions and replicated sex-associated brain-behavioral patterns, underscoring the fact that potential divergences between chronotype traits observed throughout adulthood may begin to emerge early in life. These findings highlight underappreciated sources of population variation that echo the rhythm of people’s inner clock.

2025-07-28

Research Square (preprint)

doi.org

A pattern-learning algorithm associates copy number variations with brain structure and behavioural variables in an adolescent population cohort

Kuldeep Kumar

Zohra Saci

Martineau Jean-Louis

Xiaoqian J. Chai

Tian Ge

B. T. Thomas Yeo

Paul M. Thompson

Carrie E. Bearden

Ole A. Andreassen

Sébastien Jacquemont

Danilo Bzdok

Our genetic makeup, together with environmental and social influences, shape our brain's development. Yet, the imaging-genetics field has st… (see more)ruggled to integrate all these modalities to investigate the interplay between genetic blueprint, brain architecture, environment, human health and daily living skills. Here we interrogate the Adolescent Brain Cognitive Development (ABCD) cohort to outline the effects of rare high-effect genetic variants on brain architecture and their corresponding implications on cognitive, behavioural, psychosocial and socioeconomic traits. We design a holistic pattern-learning framework that quantitatively dissects the impacts of copy number variations (CNVs) on brain structure and 938 behavioural variables spanning 20 categories in 7,338 adolescents. Our results reveal associations between genetic alterations, higher-order brain networks and specific parameters of the family wellbeing, including increased parental and child stress, anxiety and depression, or neighbourhood dynamics such as decreased safety. We thus find effects extending beyond the impairment of cognitive ability or language capacity which have been previously reported. Our investigation spotlights the interplay between genetic variation and subjective life quality in adolescents and their families.

2025-07-17

Nature Biomedical Engineering (published)

doi.org

A pattern-learning algorithm associates copy number variations with brain structure and behavioural variables in an adolescent population cohort

Kuldeep Kumar

Zohra Saci

Martineau Jean-Louis

Xiaoqian J. Chai

Tian Ge

B. T. Thomas Yeo

Paul M. Thompson

Carrie E. Bearden

Ole A. Andreassen

Sébastien Jacquemont

Danilo Bzdok

Our genetic makeup, together with environmental and social influences, shape our brain's development. Yet, the imaging-genetics field has st… (see more)ruggled to integrate all these modalities to investigate the interplay between genetic blueprint, brain architecture, environment, human health and daily living skills. Here we interrogate the Adolescent Brain Cognitive Development (ABCD) cohort to outline the effects of rare high-effect genetic variants on brain architecture and their corresponding implications on cognitive, behavioural, psychosocial and socioeconomic traits. We design a holistic pattern-learning framework that quantitatively dissects the impacts of copy number variations (CNVs) on brain structure and 938 behavioural variables spanning 20 categories in 7,338 adolescents. Our results reveal associations between genetic alterations, higher-order brain networks and specific parameters of the family wellbeing, including increased parental and child stress, anxiety and depression, or neighbourhood dynamics such as decreased safety. We thus find effects extending beyond the impairment of cognitive ability or language capacity which have been previously reported. Our investigation spotlights the interplay between genetic variation and subjective life quality in adolescents and their families.

2025-07-17

Nature Biomedical Engineering (published)

doi.org

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

Kuldeep Kumar

Zhijie Liao

Jakub Kopal

Clara Moreau

Christopher R. K. Ching

Claudia Modenato

Will Snyder

Sayeh Kazem