Beyond a Binary Classification of Sex: An Examination of Brain Sex Differentiation, Psychopathology, and Genotype

Phillips, Owen R.; Onopa, Alexander; Hsu, Vivian M.; Ollila, Hanna; Hillary, Ryan; Hallmayer, Joachim; Gotlib, Ian H.; Taylor, Jonathan; Mackey, Lester; Singh, Manpreet K.

doi:10.1016/j.jaac.2018.09.425

Cited by 20 publications

(19 citation statements)

References 58 publications

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“…Sex specific DNAm tended to be reproducible across the brain regions and 77 CpGs resulted from the cross-region intersection. Among them there are sDMPs mapping in genes that have been already associated to sex differences in brain physiology and pathology, like Par-3 Family Cell Polarity Regulator Beta ( PARD3B ) (Phillips et al, 2019 ), DEAF1 Transcription Factor ( DEAF1 ) (Luckhart et al, 2016 ), and Iodothyronine Deiodinase 3 ( DIO3 ) (Stohn et al, 2019 ) genes. Most of these 77 probes were previously reported as differentially methylated between males and females also in previous meta-analysis on blood (McCarthy et al, 2014 ; Yusipov et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

A Meta-Analysis of Brain DNA Methylation Across Sex, Age, and Alzheimer's Disease Points for Accelerated Epigenetic Aging in Neurodegeneration

Pellegrini

Pirazzini

Sala

et al. 2021

Front. Aging Neurosci.

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Alzheimer's disease (AD) is characterized by specific alterations of brain DNA methylation (DNAm) patterns. Age and sex, two major risk factors for AD, are also known to largely affect the epigenetic profiles in brain, but their contribution to AD-associated DNAm changes has been poorly investigated. In this study we considered publicly available DNAm datasets of four brain regions (temporal, frontal, entorhinal cortex, and cerebellum) from healthy adult subjects and AD patients, and performed a meta-analysis to identify sex-, age-, and AD-associated epigenetic profiles. In one of these datasets it was also possible to distinguish 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) profiles. We showed that DNAm differences between males and females tend to be shared between the four brain regions, while aging differently affects cortical regions compared to cerebellum. We found that the proportion of sex-dependent probes whose methylation is modified also during aging is higher than expected, but that differences between males and females tend to be maintained, with only a few probes showing age-by-sex interaction. We did not find significant overlaps between AD- and sex-associated probes, nor disease-by-sex interaction effects. On the contrary, we found that AD-related epigenetic modifications are significantly enriched in probes whose DNAm varies with age and that there is a high concordance between the direction of changes (hyper or hypo-methylation) in aging and AD, supporting accelerated epigenetic aging in the disease. In summary, our results suggest that age-associated DNAm patterns concur to the epigenetic deregulation observed in AD, providing new insights on how advanced age enables neurodegeneration.

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Section: Discussionmentioning

confidence: 99%

A Meta-Analysis of Brain DNA Methylation Across Sex, Age, and Alzheimer's Disease Points for Accelerated Epigenetic Aging in Neurodegeneration

Pellegrini

Pirazzini

Sala

et al. 2021

Front. Aging Neurosci.

View full text Add to dashboard Cite

show abstract

“…Sex specific DNAm tend to be reproducible across the brain regions and 77 CpGs resulted from the cross-region intersection. Among them there are sDMPs mapping in genes that have been already associated to sex differences in brain physiology and pathology, likePar-3 Family Cell Polarity Regulator Beta (PARD3B)(53), DEAF1 Transcription Factor (DEAF1)(54) and Iodothyronine Deiodinase 3 (DIO3)(55) genes. Most of these 77 probes were previously reported as differentially methylated between males and females also in previous meta-analysis on blood(56, 57).…”

Section: Discussionmentioning

confidence: 99%

A meta-analysis of brain DNA methylation across sex, age and Alzheimer’s disease points for accelerated epigenetic aging in neurodegeneration

Pellegrini

Pirazzini

Sala

et al. 2020

Preprint

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Alzheimer's disease (AD) is characterized by specific alterations of brain DNA methylation (DNAm) patterns. Age and sex, two major risk factors for AD, are also known to largely affect the epigenetic profiles in the brain, but their contribution to AD-associated DNAm changes has been poorly investigated. In this study we considered publicly available DNAm datasets of 4 brain regions (temporal, frontal, entorhinal cortex and cerebellum) from healthy adult subjects and AD patients, and performed a meta-analysis to identify sex-, age- and AD-associated epigenetic profiles. We showed that DNAm differences between males and females tend to be shared between the 4 brain regions, while aging differently affects cortical regions compared to cerebellum. We found that the proportion of sex-dependent probes whose methylation changes also during aging is higher than expected, but that differences between males and females tend to be maintained, with only few probes showing sex-by-age interaction. We did not find significant overlaps between AD- and sex-associated probes, nor disease-by-sex interaction effects. On the contrary, we found that AD-related epigenetic modifications are significantly enriched in probes whose DNAm changes with age and that there is a high concordance between the direction of changes (hyper or hypo-methylation) in aging and AD, supporting accelerated epigenetic aging in the disease. In conclusion, we demonstrated that age-associated, but not sex-associated DNAm concurs to the epigenetic deregulation observed in AD, providing new insight on how advanced age enables neurodegeneration.

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“…Previous research (Phillips et al, 2019;Tunç et al, 2016) showed some (mixed) evidence of an association between brain and behavioural differences along a male-female dimension, but ours uses two independent samples (total sample size more than double as Tunç (2016) and Phillips ( 2019)) and two different methods for deriving the brain measures, and carefully considers whether brain size may drive the brain-behaviour association. It is possible brain size could drive the association between brain and behaviour found previously, as the previous two studies (Phillips et al, 2019;Tunç et al, 2016) did not adjust (all) brain measures for brain size, and did not apply an allometric approach to consider that different brain regions scale differently to brain size. As a consequence, their brain data could still contain shape differences that are associated with the original size differences, and their score reflecting brain differences along a male-female dimension could be driven by these size differences.…”

Section: Discussionmentioning

confidence: 99%

“…and unshared environmental (40-68%) influences. Phillips et al (2019) estimated the heritability of sex-differentiated brain structure at 0-1.5% using single nucleotide polymorphism (SNP) data. SNP heritability estimates are extremely imprecise in samples of that size (N=900), and in any case SNPs typically do not capture most of the total heritability of complex traits (Wainschtein et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Are sex differences in human brain structure associated with sex differences in behaviour?

Eijk¹,

Zhu²,

Couvy‐Duchesne³

et al. 2021

Preprint

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On average, men and women differ in brain structure and behaviour, raising the possibility of a link between sex differences in brain and behaviour. But women and men are also subject to different societal and cultural norms. We navigated this challenge by investigating variability of sex-differentiated brain structure within each sex. Using data from the Queensland Twin IMaging study (N=1,040) and Human Connectome Project (N=1,113), we obtained data-driven measures of individual differences along a male-female dimension for brain and behaviour based on average sex differences in brain structure and behaviour, respectively. We found a weak association between these brain and behavioural differences, driven by brain size. These brain and behavioural differences were moderately heritable. Our findings suggest that behavioural sex differences are to some extent related to sex differences in brain structure, but that this is mainly driven by differences in brain size, and causality should be interpreted cautiously.

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Beyond a Binary Classification of Sex: An Examination of Brain Sex Differentiation, Psychopathology, and Genotype

Cited by 20 publications

References 58 publications

A Meta-Analysis of Brain DNA Methylation Across Sex, Age, and Alzheimer's Disease Points for Accelerated Epigenetic Aging in Neurodegeneration

A Meta-Analysis of Brain DNA Methylation Across Sex, Age, and Alzheimer's Disease Points for Accelerated Epigenetic Aging in Neurodegeneration

A meta-analysis of brain DNA methylation across sex, age and Alzheimer’s disease points for accelerated epigenetic aging in neurodegeneration

Are sex differences in human brain structure associated with sex differences in behaviour?

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