Karin Saltoun

Claudia Modenato

Clara Moreau

Sandra Martin‐Brevet

Guillaume Huguet

Martineau Jean‐Louis

Charles-Olivier Martin

Zohra Saci

Nadine Younis

Petra Tamer

Élise Douard

Anne Maillard

Borja Rodríguez‐Herreros

Aurélie Pain

Sonia Richetin

Leila Kushan

Ana Isabel Silva

Marianne van den Bree … (see 12 more)

David E.J. Linden

Michael 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

Copy number variations (CNVs) are rare genomic deletions and duplications that can affect brain and behaviour. Previous reports of CNV pleio… (see more)tropy imply that they converge on shared mechanisms at some level of pathway cascades, from genes to large-scale neural circuits to the phenome. However, existing studies have primarily examined single CNV loci in small clinical cohorts. It remains unknown, for example, how distinct CNVs escalate vulnerability for the same developmental and psychiatric disorders. Here we quantitatively dissect the associations between brain organization and behavioural differentiation across 8 key CNVs. In 534 CNV carriers, we explored CNV-specific brain morphology patterns. CNVs were characteristic of disparate morphological changes involving multiple large-scale networks. We extensively annotated these CNV-associated patterns with ~1,000 lifestyle indicators through the UK Biobank resource. The resulting phenotypic profiles largely overlap and have body-wide implications, including the cardiovascular, endocrine, skeletal and nervous systems. Our population-level investigation established brain structural divergences and phenotypical convergences of CNVs, with direct relevance to major brain disorders.

2023-03-01

Nature Human Behaviour (unknown)

APOE alleles are associated with sex-specific structural differences in brain regions affected in Alzheimer's disease and related dementia

Chloé Savignac

Sylvia Villeneuve

AmanPreet Badhwar

Kimia Shafighi

Chris Zajner

Vaibhav Sharma

Sarah A. Gagliano Taliun

Sali Farhan

Judes Poirier

Alzheimer’s disease is marked by intracellular tau aggregates in the medial temporal lobe (MTL) and extracellular amyloid aggregates in th… (see more)e default network (DN). Here, we examined codependent structural variations between the MTL’s most vulnerable structure, the hippocampus (HC), and the DN at subregion resolution in individuals with Alzheimer’s disease and related dementia (ADRD). By leveraging the power of the approximately 40,000 participants of the UK Biobank cohort, we assessed impacts from the protective APOE ɛ2 and the deleterious APOE ɛ4 Alzheimer’s disease alleles on these structural relationships. We demonstrate ɛ2 and ɛ4 genotype effects on the inter-individual expression of HC-DN co-variation structural patterns at the population level. Across these HC-DN signatures, recurrent deviations in the CA1, CA2/3, molecular layer, fornix’s fimbria, and their cortical partners related to ADRD risk. Analyses of the rich phenotypic profiles in the UK Biobank cohort further revealed male-specific HC-DN associations with air pollution and female-specific associations with cardiovascular traits. We also showed that APOE ɛ2/2 interacts preferentially with HC-DN co-variation patterns in estimating social lifestyle in males and physical activity in females. Our structural, genetic, and phenotypic analyses in this large epidemiological cohort reinvigorate the often-neglected interplay between APOE ɛ2 dosage and sex and link APOE alleles to inter-individual brain structural differences indicative of ADRD familial risk.

2022-11-30

PLoS Biology (published)

Dissociable brain structural asymmetry patterns reveal unique phenome-wide profiles

Ralph Adolphs

Lynn K. Paul

Vaibhav Sharma

Joern Diedrichsen

B. T. Thomas Yeo

2022-11-06

Nature Human Behaviour (unknown)

<i>APOE</i> ɛ2 vs <i>APOE</i> ɛ4 dosage shows sex-specific links to hippocampus-default network subregion co-variation

Chloé Savignac

Sylvia Villeneuve

AmanPreet Badhwar

Kimia Shafighi

Chris Zajner

Vaibhav Sharma

Sarah A Gagliano Taliun

Sali Farhan

Judes Poirier

Alzheimer’s disease and related dementias (ADRD) are marked by intracellular tau aggregates in the medial-temporal lobe (MTL) and extracel… (see more)lular amyloid aggregates in the default network (DN). Here, we sought to clarify ADRD-related co-dependencies between the MTL’s most vulnerable structure, the hippocampus (HC), and the highly associative DN at a subregion resolution. We confronted the effects of APOE ɛ2 and ɛ4, rarely investigated together, with their impact on HC-DN co-variation regimes at the population level. In a two-pronged decomposition of structural brain scans from ∼40,000 UK Biobank participants, we located co-deviating structural patterns in HC and DN subregions as a function of ADRD family risk. Across the disclosed HC-DN signatures, recurrent deviations in the CA1, CA2/3, molecular layer, fornix’s fimbria, and their cortical partners related to ADRD risk. Phenome-wide profiling of HC-DN co- variation expressions from these population signatures revealed male-specific associations with air-pollution, and female-specific associations with cardiovascular traits. We highlighted three main factors associated with brain-APOE associations across the different gene variants: happiness, and satisfaction with friendships, and with family. We further showed that APOE ɛ2/2 interacts preferentially with HC-DN co-variation patterns in estimating social lifestyle in males and physical activity in females. Our findings reinvigorate the often-neglected interplay between APOE ɛ2 dosage and sex, which we have linked to fine-grained structural divergences indicative of ADRD susceptibility.

2022-03-14

bioRxiv (preprint)