Publications
41. Paquola, Casey; Seidlitz, Jakob; Benkarim, Oualid; Royer, Jessica; Klimes, Petr; Bethlehem, Richard A I; Larivière, Sara; de Wael, Reinder Vos; Rodríguez-Cruces, Raul; Hall, Jeffery A; Frauscher, Birgit; Smallwood, Jonathan; Bernhardt, Boris C
A multi-scale cortical wiring space links cellular architecture
and functional dynamics in the human brain Journal Article
In: PLoS Biol., vol. 18, no. 11, pp. e3000979, 2020.
@article{Paquola2020-gb,
title = {A multi-scale cortical wiring space links cellular architecture
and functional dynamics in the human brain},
author = {Casey Paquola and Jakob Seidlitz and Oualid Benkarim and Jessica Royer and Petr Klimes and Richard A I Bethlehem and Sara Larivière and Reinder Vos de Wael and Raul Rodríguez-Cruces and Jeffery A Hall and Birgit Frauscher and Jonathan Smallwood and Boris C Bernhardt},
year = {2020},
date = {2020-11-01},
journal = {PLoS Biol.},
volume = {18},
number = {11},
pages = {e3000979},
publisher = {Public Library of Science (PLoS)},
abstract = {The vast net of fibres within and underneath the cortex is
optimised to support the convergence of different levels of
brain organisation. Here, we propose a novel coordinate system
of the human cortex based on an advanced model of its
connectivity. Our approach is inspired by seminal, but so far
largely neglected models of cortico-cortical wiring established
by postmortem anatomical studies and capitalises on cutting-edge
in vivo neuroimaging and machine learning. The new model expands
the currently prevailing diffusion magnetic resonance imaging
(MRI) tractography approach by incorporation of additional
features of cortical microstructure and cortico-cortical
proximity. Studying several datasets and different parcellation
schemes, we could show that our coordinate system robustly
recapitulates established sensory-limbic and anterior-posterior
dimensions of brain organisation. A series of validation
experiments showed that the new wiring space reflects cortical
microcircuit features (including pyramidal neuron depth and
glial expression) and allowed for competitive simulations of
functional connectivity and dynamics based on resting-state
functional magnetic resonance imaging (rs-fMRI) and human
intracranial electroencephalography (EEG) coherence. Our results
advance our understanding of how cell-specific neurobiological
gradients produce a hierarchical cortical wiring scheme that is
concordant with increasing functional sophistication of human
brain organisation. Our evaluations demonstrate the cortical
wiring space bridges across scales of neural organisation and
can be easily translated to single individuals.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The vast net of fibres within and underneath the cortex is
optimised to support the convergence of different levels of
brain organisation. Here, we propose a novel coordinate system
of the human cortex based on an advanced model of its
connectivity. Our approach is inspired by seminal, but so far
largely neglected models of cortico-cortical wiring established
by postmortem anatomical studies and capitalises on cutting-edge
in vivo neuroimaging and machine learning. The new model expands
the currently prevailing diffusion magnetic resonance imaging
(MRI) tractography approach by incorporation of additional
features of cortical microstructure and cortico-cortical
proximity. Studying several datasets and different parcellation
schemes, we could show that our coordinate system robustly
recapitulates established sensory-limbic and anterior-posterior
dimensions of brain organisation. A series of validation
experiments showed that the new wiring space reflects cortical
microcircuit features (including pyramidal neuron depth and
glial expression) and allowed for competitive simulations of
functional connectivity and dynamics based on resting-state
functional magnetic resonance imaging (rs-fMRI) and human
intracranial electroencephalography (EEG) coherence. Our results
advance our understanding of how cell-specific neurobiological
gradients produce a hierarchical cortical wiring scheme that is
concordant with increasing functional sophistication of human
brain organisation. Our evaluations demonstrate the cortical
wiring space bridges across scales of neural organisation and
can be easily translated to single individuals.42. Holla, Bharath; Seidlitz, Jakob; Bethlehem, Richard A I; Schumann, Gunter
Population normative models of human brain growth across
development Journal Article
In: Sci. Bull. (Beijing), vol. 65, no. 22, pp. 1872–1873, 2020.
BibTeX | Tags:
@article{Holla2020-ek,
title = {Population normative models of human brain growth across
development},
author = {Bharath Holla and Jakob Seidlitz and Richard A I Bethlehem and Gunter Schumann},
year = {2020},
date = {2020-11-01},
journal = {Sci. Bull. (Beijing)},
volume = {65},
number = {22},
pages = {1872–1873},
publisher = {Elsevier BV},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
43. Seidlitz, Jakob; Nadig, Ajay; Liu, Siyuan; Bethlehem, Richard A I; Vértes, Petra E; Morgan, Sarah E; Váša, František; Romero-Garcia, Rafael; Lalonde, François M; Clasen, Liv S; Blumenthal, Jonathan D; Paquola, Casey; Bernhardt, Boris; Wagstyl, Konrad; Polioudakis, Damon; Torre-Ubieta, Luis; Geschwind, Daniel H; Han, Joan C; Lee, Nancy R; Murphy, Declan G; Bullmore, Edward T; Raznahan, Armin
Author Correction: Transcriptomic and cellular decoding of
regional brain vulnerability to neurogenetic disorders Journal Article
In: Nat. Commun., vol. 11, no. 1, pp. 5936, 2020.
@article{Seidlitz2020-sd,
title = {Author Correction: Transcriptomic and cellular decoding of
regional brain vulnerability to neurogenetic disorders},
author = {Jakob Seidlitz and Ajay Nadig and Siyuan Liu and Richard A I Bethlehem and Petra E Vértes and Sarah E Morgan and František Váša and Rafael Romero-Garcia and François M Lalonde and Liv S Clasen and Jonathan D Blumenthal and Casey Paquola and Boris Bernhardt and Konrad Wagstyl and Damon Polioudakis and Luis Torre-Ubieta and Daniel H Geschwind and Joan C Han and Nancy R Lee and Declan G Murphy and Edward T Bullmore and Armin Raznahan},
year = {2020},
date = {2020-11-01},
journal = {Nat. Commun.},
volume = {11},
number = {1},
pages = {5936},
publisher = {Springer Science and Business Media LLC},
abstract = {An amendment to this paper has been published and can be
accessed via a link at the top of the paper.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
An amendment to this paper has been published and can be
accessed via a link at the top of the paper.44. Bethlehem, Richard A I; Paquola, Casey; Seidlitz, Jakob; Ronan, Lisa; Bernhardt, Boris; Consortium, Cam-Can; Tsvetanov, Kamen A
Dispersion of functional gradients across the adult lifespan Journal Article
In: Neuroimage, vol. 222, no. 117299, pp. 117299, 2020.
@article{Bethlehem2020-bs,
title = {Dispersion of functional gradients across the adult lifespan},
author = {Richard A I Bethlehem and Casey Paquola and Jakob Seidlitz and Lisa Ronan and Boris Bernhardt and Cam-Can Consortium and Kamen A Tsvetanov},
year = {2020},
date = {2020-11-01},
journal = {Neuroimage},
volume = {222},
number = {117299},
pages = {117299},
publisher = {Elsevier BV},
abstract = {Ageing is commonly associated with changes to segregation and
integration of functional brain networks, but, in isolation,
current network-based approaches struggle to elucidate changes
across the many axes of functional organisation. However, the
advent of gradient mapping techniques in neuroimaging provides a
new means of studying functional organisation in a
multi-dimensional connectivity space. Here, we studied ageing
and behaviourally-relevant differences in a three-dimensional
connectivity space using the Cambridge Centre for Ageing Neuroscience cohort (n = 643). Building on gradient mapping
techniques, we developed a set of measures to quantify the
dispersion within and between functional communities. We
detected a strong shift of the visual network across the adult
lifespan from an extreme to a more central position in the 3D
gradient space. In contrast, the dispersion distance between
transmodal communities (dorsal attention, ventral attention,
frontoparietal and default mode) did not change. However, these
communities themselves were increasingly dispersed with
increasing age, reflecting more dissimilar functional
connectivity profiles within each community. Increasing
dispersion of frontoparietal, attention and default mode
networks, in particular, were associated negatively with
cognition, measured by fluid intelligence. By using a technique
that explicitly captures the ordering of functional systems in a
multi-dimensional hierarchical framework, we identified
behaviorally-relevant age-related differences of within and
between network organisation. We propose that the study of
functional gradients across the adult lifespan could provide
insights that may facilitate the development of new strategies
to maintain cognitive ability across the lifespan in health and
disease.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Ageing is commonly associated with changes to segregation and
integration of functional brain networks, but, in isolation,
current network-based approaches struggle to elucidate changes
across the many axes of functional organisation. However, the
advent of gradient mapping techniques in neuroimaging provides a
new means of studying functional organisation in a
multi-dimensional connectivity space. Here, we studied ageing
and behaviourally-relevant differences in a three-dimensional
connectivity space using the Cambridge Centre for Ageing Neuroscience cohort (n = 643). Building on gradient mapping
techniques, we developed a set of measures to quantify the
dispersion within and between functional communities. We
detected a strong shift of the visual network across the adult
lifespan from an extreme to a more central position in the 3D
gradient space. In contrast, the dispersion distance between
transmodal communities (dorsal attention, ventral attention,
frontoparietal and default mode) did not change. However, these
communities themselves were increasingly dispersed with
increasing age, reflecting more dissimilar functional
connectivity profiles within each community. Increasing
dispersion of frontoparietal, attention and default mode
networks, in particular, were associated negatively with
cognition, measured by fluid intelligence. By using a technique
that explicitly captures the ordering of functional systems in a
multi-dimensional hierarchical framework, we identified
behaviorally-relevant age-related differences of within and
between network organisation. We propose that the study of
functional gradients across the adult lifespan could provide
insights that may facilitate the development of new strategies
to maintain cognitive ability across the lifespan in health and
disease.45. Bethlehem, Richard A I; Seidlitz, Jakob; Romero-Garcia, Rafael; Trakoshis, Stavros; Dumas, Guillaume; Lombardo, Michael V
A normative modelling approach reveals age-atypical cortical
thickness in a subgroup of males with autism spectrum disorder Journal Article
In: Commun. Biol., vol. 3, no. 1, pp. 486, 2020.
@article{Bethlehem2020-ng,
title = {A normative modelling approach reveals age-atypical cortical
thickness in a subgroup of males with autism spectrum disorder},
author = {Richard A I Bethlehem and Jakob Seidlitz and Rafael Romero-Garcia and Stavros Trakoshis and Guillaume Dumas and Michael V Lombardo},
year = {2020},
date = {2020-09-01},
journal = {Commun. Biol.},
volume = {3},
number = {1},
pages = {486},
publisher = {Springer Science and Business Media LLC},
abstract = {Understanding heterogeneity is an important goal on the path to
precision medicine for autism spectrum disorders (ASD). We
examined how cortical thickness (CT) in ASD can be parameterized
as an individualized metric of atypicality relative to
typically-developing (TD) age-related norms. Across a large sample (n = 870 per group) and wide age range (5-40 years), we
applied normative modelling resulting in individualized
whole-brain maps of age-related CT atypicality in ASD and
isolating a small subgroup with highly age-atypical CT.
Age-normed CT scores also highlights on-average differentiation,
and associations with behavioural symptomatology that is
separate from insights gleaned from traditional case-control
approaches. This work showcases an individualized approach for
understanding ASD heterogeneity that could potentially further
prioritize work on a subset of individuals with cortical
pathophysiology represented in age-related CT atypicality. Only
a small subset of ASD individuals are actually highly atypical
relative to age-norms. driving small on-average case-control
differences.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Understanding heterogeneity is an important goal on the path to
precision medicine for autism spectrum disorders (ASD). We
examined how cortical thickness (CT) in ASD can be parameterized
as an individualized metric of atypicality relative to
typically-developing (TD) age-related norms. Across a large sample (n = 870 per group) and wide age range (5-40 years), we
applied normative modelling resulting in individualized
whole-brain maps of age-related CT atypicality in ASD and
isolating a small subgroup with highly age-atypical CT.
Age-normed CT scores also highlights on-average differentiation,
and associations with behavioural symptomatology that is
separate from insights gleaned from traditional case-control
approaches. This work showcases an individualized approach for
understanding ASD heterogeneity that could potentially further
prioritize work on a subset of individuals with cortical
pathophysiology represented in age-related CT atypicality. Only
a small subset of ASD individuals are actually highly atypical
relative to age-norms. driving small on-average case-control
differences.46. Lombardo, Michael V; Auyeung, Bonnie; Pramparo, Tiziano; Quartier, Angélique; Courraud, Jérémie; Holt, Rosemary J; Waldman, Jack; Ruigrok, Amber N V; Mooney, Natasha; Bethlehem, Richard A I; Lai, Meng-Chuan; Kundu, Prantik; Bullmore, Edward T; Mandel, Jean-Louis; Piton, Amélie; Baron-Cohen, Simon
Sex-specific impact of prenatal androgens on social brain
default mode subsystems Journal Article
In: Mol. Psychiatry, vol. 25, no. 9, pp. 2175–2188, 2020.
@article{Lombardo2020-ze,
title = {Sex-specific impact of prenatal androgens on social brain
default mode subsystems},
author = {Michael V Lombardo and Bonnie Auyeung and Tiziano Pramparo and Angélique Quartier and Jérémie Courraud and Rosemary J Holt and Jack Waldman and Amber N V Ruigrok and Natasha Mooney and Richard A I Bethlehem and Meng-Chuan Lai and Prantik Kundu and Edward T Bullmore and Jean-Louis Mandel and Amélie Piton and Simon Baron-Cohen},
year = {2020},
date = {2020-09-01},
journal = {Mol. Psychiatry},
volume = {25},
number = {9},
pages = {2175–2188},
publisher = {Springer Science and Business Media LLC},
abstract = {Early-onset neurodevelopmental conditions (e.g., autism) affect
males more frequently than females. Androgens may play a role in
this male-bias by sex-differentially impacting early prenatal
brain development, particularly neural circuits that later
develop specialized roles in social cognition. Here, we find
that increasing prenatal testosterone in humans is associated
with later reduction of functional connectivity between social
brain default mode (DMN) subsystems in adolescent males, but has
no effect in females. Since testosterone can work directly via
the androgen receptor (AR) or indirectly via the estrogen
receptor through aromatase conversion to estradiol, we further
examined how a potent non-aromatizable androgen,
dihydrotestosterone (DHT), acts via the AR to influence gene
expression in human neural stem cells (hNSC)-particularly for
genes of high-relevance for DMN circuitry. DHT dysregulates a
number of genes enriched for syndromic causes of autism and
intellectual disability and for genes that in later development
are expressed in anatomical patterns that highly correspond to
the cortical midline DMN subsystem. DMN-related and DHT-affected
genes (e.g., MEF2C) are involved in a number of synaptic
processes, many of which impact excitation-inhibition balance.
Androgens have male-specific prenatal influence over social
brain circuitry in humans and may be relevant towards explaining
some component of male-bias in early-onset neurodevelopmental
conditions.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Early-onset neurodevelopmental conditions (e.g., autism) affect
males more frequently than females. Androgens may play a role in
this male-bias by sex-differentially impacting early prenatal
brain development, particularly neural circuits that later
develop specialized roles in social cognition. Here, we find
that increasing prenatal testosterone in humans is associated
with later reduction of functional connectivity between social
brain default mode (DMN) subsystems in adolescent males, but has
no effect in females. Since testosterone can work directly via
the androgen receptor (AR) or indirectly via the estrogen
receptor through aromatase conversion to estradiol, we further
examined how a potent non-aromatizable androgen,
dihydrotestosterone (DHT), acts via the AR to influence gene
expression in human neural stem cells (hNSC)-particularly for
genes of high-relevance for DMN circuitry. DHT dysregulates a
number of genes enriched for syndromic causes of autism and
intellectual disability and for genes that in later development
are expressed in anatomical patterns that highly correspond to
the cortical midline DMN subsystem. DMN-related and DHT-affected
genes (e.g., MEF2C) are involved in a number of synaptic
processes, many of which impact excitation-inhibition balance.
Androgens have male-specific prenatal influence over social
brain circuitry in humans and may be relevant towards explaining
some component of male-bias in early-onset neurodevelopmental
conditions.47. Seidlitz, Jakob; Nadig, Ajay; Liu, Siyuan; Bethlehem, Richard A I; Vértes, Petra E; Morgan, Sarah E; Váša, František; Romero-Garcia, Rafael; Lalonde, François M; Clasen, Liv S; Blumenthal, Jonathan D; Paquola, Casey; Bernhardt, Boris; Wagstyl, Konrad; Polioudakis, Damon; Torre-Ubieta, Luis; Geschwind, Daniel H; Han, Joan C; Lee, Nancy R; Murphy, Declan G; Bullmore, Edward T; Raznahan, Armin
Transcriptomic and cellular decoding of regional brain
vulnerability to neurogenetic disorders Journal Article
In: Nat. Commun., vol. 11, no. 1, pp. 3358, 2020.
@article{Seidlitz2020-en,
title = {Transcriptomic and cellular decoding of regional brain
vulnerability to neurogenetic disorders},
author = {Jakob Seidlitz and Ajay Nadig and Siyuan Liu and Richard A I Bethlehem and Petra E Vértes and Sarah E Morgan and František Váša and Rafael Romero-Garcia and François M Lalonde and Liv S Clasen and Jonathan D Blumenthal and Casey Paquola and Boris Bernhardt and Konrad Wagstyl and Damon Polioudakis and Luis Torre-Ubieta and Daniel H Geschwind and Joan C Han and Nancy R Lee and Declan G Murphy and Edward T Bullmore and Armin Raznahan},
year = {2020},
date = {2020-07-01},
journal = {Nat. Commun.},
volume = {11},
number = {1},
pages = {3358},
publisher = {Springer Science and Business Media LLC},
abstract = {Neurodevelopmental disorders have a heritable component and are
associated with region specific alterations in brain anatomy.
However, it is unclear how genetic risks for neurodevelopmental
disorders are translated into spatially patterned brain
vulnerabilities. Here, we integrated cortical neuroimaging data
from patients with neurodevelopmental disorders caused by
genomic copy number variations (CNVs) and gene expression data
from healthy subjects. For each of the six investigated
disorders, we show that spatial patterns of cortical anatomy
changes in youth are correlated with cortical spatial expression
of CNV genes in neurotypical adults. By transforming normative
bulk-tissue cortical expression data into cell-type expression
maps, we link anatomical change maps in each analysed disorder
to specific cell classes as well as the CNV-region genes they
express. Our findings reveal organizing principles that regulate
the mapping of genetic risks onto regional brain changes in
neurogenetic disorders. Our findings will enable screening for
candidate molecular mechanisms from readily available
neuroimaging data.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Neurodevelopmental disorders have a heritable component and are
associated with region specific alterations in brain anatomy.
However, it is unclear how genetic risks for neurodevelopmental
disorders are translated into spatially patterned brain
vulnerabilities. Here, we integrated cortical neuroimaging data
from patients with neurodevelopmental disorders caused by
genomic copy number variations (CNVs) and gene expression data
from healthy subjects. For each of the six investigated
disorders, we show that spatial patterns of cortical anatomy
changes in youth are correlated with cortical spatial expression
of CNV genes in neurotypical adults. By transforming normative
bulk-tissue cortical expression data into cell-type expression
maps, we link anatomical change maps in each analysed disorder
to specific cell classes as well as the CNV-region genes they
express. Our findings reveal organizing principles that regulate
the mapping of genetic risks onto regional brain changes in
neurogenetic disorders. Our findings will enable screening for
candidate molecular mechanisms from readily available
neuroimaging data.48. Procyshyn, Tanya L; Lombardo, Michael V; Lai, Meng-Chuan; Auyeung, Bonnie; Crockford, Sarah K; Deakin, J; Soubramanian, S; Sule, A; Baron-Cohen, Simon; Bethlehem, Richard A I
Effects of oxytocin administration on salivary sex hormone
levels in autistic and neurotypical women Journal Article
In: Mol. Autism, vol. 11, no. 1, pp. 20, 2020.
Abstract | BibTeX | Tags: Autism; Autistic women; Oestradiol; Oxytocin; Salivary hormone levels; Sex steroids; Testosterone
@article{Procyshyn2020-hw,
title = {Effects of oxytocin administration on salivary sex hormone
levels in autistic and neurotypical women},
author = {Tanya L Procyshyn and Michael V Lombardo and Meng-Chuan Lai and Bonnie Auyeung and Sarah K Crockford and J Deakin and S Soubramanian and A Sule and Simon Baron-Cohen and Richard A I Bethlehem},
year = {2020},
date = {2020-03-01},
journal = {Mol. Autism},
volume = {11},
number = {1},
pages = {20},
publisher = {Springer Science and Business Media LLC},
abstract = {BACKGROUND: Oxytocin administration, which may be of therapeutic
value for individuals with social difficulties, is likely to
affect endogenous levels of other socially relevant hormones.
However, to date, the effects of oxytocin administration on
endogenous hormones have only been examined in neurotypical
individuals. The need to consider multi-hormone interactions is
particularly warranted in oxytocin trials for autism due to
evidence of irregularities in both oxytocin and sex steroid
systems. METHODS: In this double-blind cross-over study, saliva
samples were collected from 16 autistic and 29 neurotypical
women before and after intranasal administration of 24 IU
oxytocin or placebo. Oestradiol, testosterone, and oxytocin
levels were quantified in saliva samples. Participants also
completed the Autism-Spectrum Quotient (AQ) and Empathy Quotient
(EQ) questionnaires. RESULTS: Distinct patterns of change in
testosterone and oestradiol levels pre- to-post-administration
were observed in autistic relative to neurotypical women
(ANCOVA, p < 0.05 main effect of Group), controlling for sample
collection time. The mean percent change oestradiol was + 8.8%
for the autism group and - 13.0% for the neurotypical group (t = 1.8},
keywords = {Autism; Autistic women; Oestradiol; Oxytocin; Salivary hormone levels; Sex steroids; Testosterone},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: Oxytocin administration, which may be of therapeutic
value for individuals with social difficulties, is likely to
affect endogenous levels of other socially relevant hormones.
However, to date, the effects of oxytocin administration on
endogenous hormones have only been examined in neurotypical
individuals. The need to consider multi-hormone interactions is
particularly warranted in oxytocin trials for autism due to
evidence of irregularities in both oxytocin and sex steroid
systems. METHODS: In this double-blind cross-over study, saliva
samples were collected from 16 autistic and 29 neurotypical
women before and after intranasal administration of 24 IU
oxytocin or placebo. Oestradiol, testosterone, and oxytocin
levels were quantified in saliva samples. Participants also
completed the Autism-Spectrum Quotient (AQ) and Empathy Quotient
(EQ) questionnaires. RESULTS: Distinct patterns of change in
testosterone and oestradiol levels pre- to-post-administration
were observed in autistic relative to neurotypical women
(ANCOVA, p < 0.05 main effect of Group), controlling for sample
collection time. The mean percent change oestradiol was + 8.8%
for the autism group and - 13.0% for the neurotypical group (t = 1.849. Ward, Joey; Lyall, Laura M; Bethlehem, Richard A I; Ferguson, Amy; Strawbridge, Rona J; Lyall, Donald M; Cullen, Breda; Graham, Nicholas; Johnston, Keira J A; Bailey, Mark E S; Murray, Graham K; Smith, Daniel J
Novel genome-wide associations for anhedonia, genetic
correlation with psychiatric disorders, and polygenic
association with brain structure Journal Article
In: Transl. Psychiatry, vol. 9, no. 1, pp. 327, 2019.
@article{Ward2019-ri,
title = {Novel genome-wide associations for anhedonia, genetic
correlation with psychiatric disorders, and polygenic
association with brain structure},
author = {Joey Ward and Laura M Lyall and Richard A I Bethlehem and Amy Ferguson and Rona J Strawbridge and Donald M Lyall and Breda Cullen and Nicholas Graham and Keira J A Johnston and Mark E S Bailey and Graham K Murray and Daniel J Smith},
year = {2019},
date = {2019-12-01},
journal = {Transl. Psychiatry},
volume = {9},
number = {1},
pages = {327},
publisher = {Springer Science and Business Media LLC},
abstract = {Anhedonia is a core symptom of several psychiatric disorders but
its biological underpinnings are poorly understood. We performed
a genome-wide association study of state anhedonia in 375,275 UK
Biobank participants and assessed for genetic correlation
between anhedonia and neuropsychiatric conditions (major
depressive disorder, schizophrenia, bipolar disorder, obsessive
compulsive disorder and Parkinson's Disease). We then used a
polygenic risk score approach to test for association between
genetic loading for anhedonia and both brain structure and brain
function. This included: magnetic resonance imaging (MRI)
assessments of total grey matter volume, white matter volume,
cerebrospinal fluid volume, and 15 cortical/subcortical regions
of interest; diffusion tensor imaging (DTI) measures of white
matter tract integrity; and functional MRI activity during an
emotion processing task. We identified 11 novel loci associated
at genome-wide significance with anhedonia, with a SNP
heritability estimate (h2SNP) of 5.6%. Strong positive genetic
correlations were found between anhedonia and major depressive
disorder, schizophrenia and bipolar disorder; but not with
obsessive compulsive disorder or Parkinson's Disease. Polygenic
risk for anhedonia was associated with poorer brain white matter
integrity, smaller total grey matter volume, and smaller volumes
of brain regions linked to reward and pleasure processing,
including orbito-frontal cortex. In summary, the identification
of novel anhedonia-associated loci substantially expands our
current understanding of the biological basis of state anhedonia
and genetic correlations with several psychiatric disorders
confirm the utility of this phenotype as a transdiagnostic
marker of vulnerability to mental illness. We also provide the
first evidence that genetic risk for state anhedonia influences
brain structure, including in regions associated with reward and
pleasure processing.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Anhedonia is a core symptom of several psychiatric disorders but
its biological underpinnings are poorly understood. We performed
a genome-wide association study of state anhedonia in 375,275 UK
Biobank participants and assessed for genetic correlation
between anhedonia and neuropsychiatric conditions (major
depressive disorder, schizophrenia, bipolar disorder, obsessive
compulsive disorder and Parkinson's Disease). We then used a
polygenic risk score approach to test for association between
genetic loading for anhedonia and both brain structure and brain
function. This included: magnetic resonance imaging (MRI)
assessments of total grey matter volume, white matter volume,
cerebrospinal fluid volume, and 15 cortical/subcortical regions
of interest; diffusion tensor imaging (DTI) measures of white
matter tract integrity; and functional MRI activity during an
emotion processing task. We identified 11 novel loci associated
at genome-wide significance with anhedonia, with a SNP
heritability estimate (h2SNP) of 5.6%. Strong positive genetic
correlations were found between anhedonia and major depressive
disorder, schizophrenia and bipolar disorder; but not with
obsessive compulsive disorder or Parkinson's Disease. Polygenic
risk for anhedonia was associated with poorer brain white matter
integrity, smaller total grey matter volume, and smaller volumes
of brain regions linked to reward and pleasure processing,
including orbito-frontal cortex. In summary, the identification
of novel anhedonia-associated loci substantially expands our
current understanding of the biological basis of state anhedonia
and genetic correlations with several psychiatric disorders
confirm the utility of this phenotype as a transdiagnostic
marker of vulnerability to mental illness. We also provide the
first evidence that genetic risk for state anhedonia influences
brain structure, including in regions associated with reward and
pleasure processing.