@article{pmid38677627,

title = {Examining the associations between microglia genetic capacity, early life exposures and white matter development at the level of the individual},

author = {Shi Yu Chan and Eamon Fitzgerald and Zhen Ming Ngoh and Janice Lee and Jasmine Chuah and Joanne S M Chia and Marielle V Fortier and Elizabeth H Tham and Juan H Zhou and Patricia P Silveira and Michael J Meaney and Ai Peng Tan},

doi = {10.1016/j.bbi.2024.04.038},

issn = {1090-2139},

year  = {2024},

date = {2024-07-01},

journal = {Brain Behav Immun},

volume = {119},

pages = {781--791},

abstract = {There are inter-individual differences in susceptibility to the influence of early life experiences for which the underlying neurobiological mechanisms are poorly understood. Microglia play a role in environmental surveillance and may influence individual susceptibility to environmental factors. As an index of neurodevelopment, we estimated individual slopes of mean white matter fractional anisotropy (WM-FA) across three time-points (age 4.5, 6.0, and 7.5 years) for 351 participants. Individual variation in microglia reactivity was derived from an expression-based polygenic score(ePGS) comprised of Single Nucleotide Polymorphisms (SNPs) functionally related to the expression of microglia-enriched genes.A higher ePGS denotes an increased genetic capacity for the expression of microglia-related genes, and thus may confer a greater capacity to respond to the early environment and to influence brain development. We hypothesized that this ePGS would associate with the WM-FA index of neurodevelopment and moderate the influence of early environmental factors.Our findings show sex dependency, where a significant association between WM-FA and microglia ePGS was only obtained for females.We then examined associations with perinatal factors known to decrease (optimal birth outcomes and familial conditions) or increase (systemic inflammation) the risk for later mental health problems.In females, individuals with high microglia ePGS showed a negative association between systemic inflammation and WM-FA and a positive association between more advantageous environmental conditions and WM-FA. The microglia ePGS in females thus accounted for variations in the influence of the quality of the early environment on WM-FA.Finally, WM-FA slopes mediated the association of microglia ePGS with interpersonal problems and social hostility in females. Our findings suggest the genetic capacity for microglia function as a potential factor underlying differential susceptibility to early life exposuresthrough influences on neurodevelopment.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37977417,

title = {Independent Prediction of Child Psychiatric Symptoms by Maternal Mental Health and Child Polygenic Risk Scores},

author = {Lawrence M Chen and Irina Pokhvisneva and Marius Lahti-Pulkkinen and Tuomas Kvist and Jessie R Baldwin and Carine Parent and Patricia P Silveira and Jari Lahti and Katri Räikkönen and Vivette Glover and Thomas G O'Connor and Michael J Meaney and Kieran J O'Donnell},

doi = {10.1016/j.jaac.2023.08.018},

issn = {1527-5418},

year  = {2024},

date = {2024-06-01},

journal = {J Am Acad Child Adolesc Psychiatry},

volume = {63},

number = {6},

pages = {640--651},

abstract = {OBJECTIVE: Prenatal maternal symptoms of depression and anxiety are associated with an increased risk for child socioemotional and behavioral difficulties, supporting the fetal origins of mental health hypothesis. However, to date, studies have not considered specific genomic risk as a possible confound.nnMETHOD: The Avon Longitudinal Study of Parents and Children (ALSPAC) cohort (n = 5,546) was used to test if child polygenic risk score for attention-deficit/hyperactivity disorder (ADHD), schizophrenia, or depression confounds or modifies the impact of prenatal maternal depression and anxiety on child internalizing, externalizing, and total emotional/behavioral symptoms from age 4 to 16 years. Longitudinal child and adolescent symptom data were analyzed in the ALSPAC cohort using generalized estimating equations. Replication analyses were done in an independent cohort (Prevention of Preeclampsia and Intrauterine Growth Restriction [PREDO] cohort; n = 514) from Finland, which provided complementary measures of maternal mental health and child psychiatric symptoms.nnRESULTS: Maternal depression and anxiety and child polygenic risk scores independently and additively predicted behavioral and emotional symptoms from childhood through mid-adolescence. There was a robust prediction of child and adolescent symptoms from both prenatal maternal depression (generalized estimating equation estimate = 0.093, 95% CI 0.065-0.121, p = 2.66 × 10) and anxiety (generalized estimating equation estimate = 0.065, 95% CI 0.037-0.093, p = 1.62 × 10) after adjusting for child genomic risk for mental disorders. There was a similar independent effect of maternal depression (B = 0.156, 95% CI 0.066-0.246, p = .001) on child symptoms in the PREDO cohort. Genetically informed sensitivity analyses suggest that shared genetic risk only partially explains the reported association between prenatal maternal depression and offspring mental health.nnCONCLUSION: These findings highlight the genomic contribution to the fetal origins of mental health hypothesis and further evidence that prenatal maternal depression and anxiety are robust in utero risks for child and adolescent psychiatric symptoms.nnPLAIN LANGUAGE SUMMARY: Depression and anxiety affect approximately 15% of pregnant women, and children exposed to maternal depression or anxiety during pregnancy are at higher risk of developing mental health problems. However, the degree to which shared genetics explains the association between maternal and child mental health is unknown. In this study the authors generated polygenic risk scores (PRS), which provide a single measure of genetic risk for complex traits, to investigate the impact of shared genetic risk on the development of childhood mental health problems. Utilizing two longitudinal studies (n = 6,060), the authors found that PRS only partially explained the association between prenatal maternal depression and childhood mental health problems. These analyses show prenatal maternal depression remained a significant predictor of childhood mental health problems after accounting for shared genetic risk, further highlighting that prenatal maternal mental health is a robust predictor of child and adolescent mental health problems.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38233512,

title = {Associations between Social Adversity and Biomarkers of Inflammation, Stress, and Aging in Children},

author = {Matthew S Pantell and Patricia P Silveira and Euclides José de Mendonça Filho and Holly Wing and Erika M Brown and Victoria F Keeton and Irina Pokhvisneva and Kieran J O'Donnell and John Neuhaus and Danielle Hessler and Michael J Meaney and Nancy E Adler and Laura M Gottlieb},

doi = {10.1038/s41390-023-02992-6},

issn = {1530-0447},

year  = {2024},

date = {2024-05-01},

journal = {Pediatr Res},

volume = {95},

number = {6},

pages = {1553--1563},

abstract = {BACKGROUND: Prior work has found relationships between childhood social adversity and biomarkers of stress, but knowledge gaps remain. To help address these gaps, we explored associations between social adversity and biomarkers of inflammation (interleukin-1β [IL-1β], IL-6, IL-8, tumor necrosis factor-alpha [TNF-α], and salivary cytokine hierarchical "clusters" based on the three interleukins), neuroendocrine function (cortisol, cortisone, dehydroepiandrosterone, testosterone, and progesterone), neuromodulation (N-arachidonoylethanolamine, stearoylethanolamine, oleoylethanolamide, and palmitoylethanolamide), and epigenetic aging (Pediatric-Buccal-Epigenetic clock).nnMETHODS: We collected biomarker samples of children ages 0-17 recruited from an acute care pediatrics clinic and examined their associations with caregiver-endorsed education, income, social risk factors, and cumulative adversity. We calculated regression-adjusted means for each biomarker and compared associations with social factors using Wald tests. We used logistic regression to predict being in the highest cytokine cluster based on social predictors.nnRESULTS: Our final sample included 537 children but varied based on each biomarker. Cumulative social adversity was significantly associated with having higher levels of all inflammatory markers and with cortisol, displaying a U-shaped distribution. There were no significant relationships between cumulative social adversity and cortisone, neuromodulation biomarkers or epigenetic aging.nnCONCLUSION: Our findings support prior work suggesting that social stress exposures contribute to increased inflammation in children.nnIMPACT: Our study is one of the largest studies examining associations between childhood social adversity and biomarkers of inflammation, neuroendocrine function, neuromodulation, and epigenetic aging. It is one of the largest studies to link childhood social adversity to biomarkers of inflammation, and the first of which we are aware to link cumulative social adversity to cytokine clusters. It is also one of the largest studies to examine associations between steroids and epigenetic aging among children, and one of the only studies of which we are aware to examine associations between social adversity and endocannabinoids among children.nnCLINICAL TRIAL REGISTRATION: NCT02746393.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38372503,

title = {The impact of poor fetal growth and chronic hyperpalatable diet exposure in adulthood on hippocampal function and feeding patterns in male rats},

author = {Amanda Brondani Mucellini and Daniela Pereira Laureano and Márcio Bonesso Alves and Roberta Dalle Molle and Mariana Balbinot Borges and Ana Paula da Ascenção Salvador and Irina Pokhvisneva and Gisele Gus Manfro and Patrícia Pelufo Silveira},

doi = {10.1002/dev.22459},

issn = {1098-2302},

year  = {2024},

date = {2024-02-01},

journal = {Dev Psychobiol},

volume = {66},

number = {2},

pages = {e22459},

abstract = {Poor fetal growth affects eating behavior and the mesocorticolimbic system; however, its influence on the hippocampus has been less explored. Brain insulin sensitivity has been linked to developmental plasticity in response to fetal adversity and to cognitive performance following high-fat diet intake. We investigated whether poor fetal growth and exposure to chronic hyperpalatable food in adulthood could influence the recognition of environmental and food cues, eating behavior patterns, and hippocampal insulin signaling. At 60 days of life, we assigned male offspring from a prenatal animal model of 50% food restriction (FR) to receive either a high-fat and -sugar (HFS) diet or standard chow (CON) diet. Behavioral tests were conducted at 140 days, then tissues were collected. HFS groups showed a diminished hippocampal pAkt/Akt ratio. FR-CON and FR-HFS groups had higher levels of suppressor of cytokine signaling 3, compared to control groups. FR groups showed increased exploration of a novel hyperpalatable food, independent of their diet, and HFS groups exhibited overall lower entropy (less random, more predictable eating behavior) when the environment changed. Poor fetal growth and chronic HFS diet in adulthood altered hippocampal insulin signaling and eating patterns, diminishing the flexibility associated with eating behavior in response to extrinsic changes in food availability in the environment.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38177108,

title = {Parental and child genetic burden of glycaemic dysregulation and early-life cognitive development: an Asian and European prospective cohort study},

author = {Jian Huang and Michelle Z L Kee and Evelyn C Law and Ka Kei Sum and Patricia Pelufo Silveira and Keith M Godfrey and Lourdes Mary Daniel and Kok Hian Tan and Yap Seng Chong and Shiao-Yng Chan and Johan G Eriksson and Michael J Meaney and Jonathan Yinhao Huang},

doi = {10.1038/s41398-023-02694-x},

issn = {2158-3188},

year  = {2024},

date = {2024-01-01},

journal = {Transl Psychiatry},

volume = {14},

number = {1},

pages = {2},

abstract = {Insulin resistance and glucose metabolism have been associated with neurodevelopmental disorders. However, in the metabolically more susceptible Asian populations, it is not clear whether the genetic burden of glycaemic dysregulation influences early-life neurodevelopment. In a multi-ethnic Asian prospective cohort study in Singapore (Growing Up in Singapore Towards healthy Outcomes (GUSTO)), we constructed child and parental polygenic risk scores (PRS) for glycaemic dysregulation based on the largest genome-wide association studies of type 2 diabetes and fasting glucose among Asians. We found that child PRS for HOMA-IR was associated with a lower perceptual reasoning score at ~7 years (β = -0. 141, p-value = 0.024, 95% CI -0. 264 to -0. 018) and a lower WIAT-III mean score at ~9 years (β = -0.222, p-value = 0.001, 95% CI -0.357 to -0.087). This association were consistent in direction among boys and girls. These inverse associations were not influenced by parental PRS and were likely mediated via insulin resistance rather than mediators such as birth weight and childhood body mass index. Higher paternal PRS for HOMA-IR was suggestively associated with lower child perceptual reasoning at ~7 years (β = -0.172, p-value = 0.002, 95% CI -0.280 to -0.064). Replication analysis in a European cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort, showed that higher child PRS for fasting glucose was associated with lower verbal IQ score while higher maternal PRS for insulin resistance was associated with lower performance IQ score in their children at ~8.5 years. In summary, our findings suggest that higher child PRS for HOMA-IR was associated with lower cognitive scores in both Asian and European replication cohorts. Differential findings between cohorts may be attributed to genetic and environmental factors. Further investigation of the functions of the genetic structure and ancestry-specific PRS and a more comprehensive investigation of behavioural mediators may help to understand these findings better.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38140734,

title = {Accumbal μ-opioid receptors and salt taste-elicited hedonic responses in a rodent model of prenatal adversity, and their correlates using human functional genomics},

author = {Adrianne Rahde Bischoff and Roberta Dalle Molle and Amanda Brondani Mucellini and Irina Pokhvisneva and Robert D Levitan and Michael J Meaney and Patrícia P Silveira},

doi = {10.1080/10253890.2023.2294954},

issn = {1607-8888},

year  = {2024},

date = {2024-01-01},

journal = {Stress},

volume = {27},

number = {1},

pages = {2294954},

abstract = {Prenatal adversity is associated with behavioral obesogenic features such as preference for palatable foods. Salt appetite may play a role in the development of adiposity and its consequences in individuals exposed to prenatal adversity, and sodium consumption involves individual differences in accumbal µ-opioid receptors function. We investigated the hedonic responses to salt and the levels of µ-opioid receptors and tyrosine hydroxylase in the nucleus accumbens (Nacc) of pups from an animal model of prenatal dietary restriction. In children, we evaluated the interaction between fetal growth and the genetic background associated with the accumbal µ-opioid receptor gene (OPRM1) expression on sodium consumption during a snack test. Sprague-Dawley dams were randomly allocated from pregnancy day 10 to receive an  (Adlib) or a 50% restricted (FR) diet. The pups' hedonic responses to a salt solution (NaCl 2%) or water were evaluated on the first day of life. FR and Adlib pups differ in their hedonic responses to salt, and there were decreased levels of accumbal µ-opioid and p-µ-opioid receptors in FR pups. In humans, a test meal and genotyping from buccal epithelial cells were performed in 270 children (38 intrauterine growth restricted-IUGR) at 4 years old from a Canadian prospective cohort (MAVAN). The OPRM1 genetic score predicted the sodium intake in IUGR children, but not in controls. The identification of mechanisms involved in the brain response to prenatal adversity and its consequences in behavioral phenotypes and risk for chronic diseases later in life is important for preventive and therapeutic purposes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37549631,

title = {Sex and cell-specific gene expression in corticolimbic brain regions associated with psychiatric disorders revealed by bulk and single-nuclei RNA sequencing},

author = {Eamon Fitzgerald and Danusa Mar Arcego and Mo Jun Shen and Nicholas O'Toole and Xianglan Wen and Corina Nagy and Sara Mostafavi and Kelly Craig and Patricia Pelufo Silveira and Nirmala Arul Rayan and Josie Diorio and Michael J Meaney and Tie-Yuan Zhang},

doi = {10.1016/j.ebiom.2023.104749},

issn = {2352-3964},

year  = {2023},

date = {2023-09-01},

journal = {EBioMedicine},

volume = {95},

pages = {104749},

abstract = {BACKGROUND: There are sex-specific differences in the prevalence, symptomology and course of psychiatric disorders. However, preclinical models have primarily used males, such that the molecular mechanisms underlying sex-specific differences in psychiatric disorders are not well established.nnMETHODS: In this study, we compared transcriptome-wide gene expression profiles in male and female rats within the corticolimbic system, including the cingulate cortex, nucleus accumbens medial shell (NAcS), ventral dentate gyrus and the basolateral amygdala (n = 22-24 per group/region).nnFINDINGS: We found over 3000 differentially expressed genes (DEGs) in the NAcS between males and females. Of these DEGs in the NAcS, 303 showed sex-dependent conservation DEGs in humans and were significantly enriched for gene ontology terms related to blood vessel morphogenesis and regulation of cell migration. Single nuclei RNA sequencing in the NAcS of male and female rats identified widespread sex-dependent expression, with genes upregulated in females showing a notable enrichment for synaptic function. Female upregulated genes in astrocytes, Drd3+MSNs and oligodendrocyte were also enriched in several psychiatric genome-wide association studies (GWAS).nnINTERPRETATION: Our data provide comprehensive evidence of sex- and cell-specific molecular profiles in the NAcS. Importantly these differences associate with anxiety, bipolar disorder, schizophrenia, and cross-disorder, suggesting an intrinsic molecular basis for sex-based differences in psychiatric disorders that strongly implicates the NAcS.nnFUNDING: This work was supported by funding from the Hope for Depression Research Foundation (MJM).},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37544390,

title = {Brain insulin signaling as a potential mediator of early life adversity effects on physical and mental health},

author = {Bonnie Alberry and Patricia Pelufo Silveira},

doi = {10.1016/j.neubiorev.2023.105350},

issn = {1873-7528},

year  = {2023},

date = {2023-08-01},

journal = {Neurosci Biobehav Rev},

volume = {153},

pages = {105350},

abstract = {In numerous brain structures, insulin signaling modulates the homeostatic processes, sensitivity to reward pathways, executive function, memory, and cognition. Through human studies and animal models, mounting evidence implicates central insulin signaling in the metabolic, physiological, and psychological consequences of early life adversity. In this review, we describe the consequences of early life adversity in the brain where insulin signaling is a key factor and how insulin may moderate the effects of adversity on psychiatric and cardio-metabolic health outcomes. Further understanding of how early life adversity and insulin signaling impact specific brain regions and mental and physical health outcomes will assist in prevention, diagnosis, and potential intervention following early life adversity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37519472,

title = {Novel Functional Genomics Approaches Bridging Neuroscience and Psychiatry},

author = {Jose M Restrepo-Lozano and Cecilia Flores and Patricia P Silveira},

doi = {10.1016/j.bpsgos.2022.07.005},

issn = {2667-1743},

year  = {2023},

date = {2023-07-01},

journal = {Biol Psychiatry Glob Open Sci},

volume = {3},

number = {3},

pages = {351--361},

abstract = {The possibility of establishing a metric of individual genetic risk for a particular disease or trait has sparked the interest of the clinical and research communities, with many groups developing and validating genomic profiling methodologies for their potential application in clinical care. Current approaches for calculating genetic risk to specific psychiatric conditions consist of aggregating genome-wide association studies-derived estimates into polygenic risk scores, which broadly represent the number of inherited risk alleles for an individual. While the traditional approach for polygenic risk score calculation aggregates estimates of gene-disease associations, novel alternative approaches have started to consider functional molecular phenotypes that are closer to genetic variation and are less penalized by the multiple testing required in genome-wide association studies. Moving the focus from genotype-disease to genotype-gene regulation frameworks, these novel approaches incorporate prior knowledge regarding biological processes involved in disease and aggregate estimates for the association of genotypes and phenotypes using multi-omics data modalities. In this review, we discuss and list different functional genomics tools that can be used and integrated to inform researchers and clinicians for a better understanding and diagnosis of psychopathology. We suggest that these novel approaches can help generate biologically driven hypotheses for polygenic signals that can ultimately serve the clinical community as potential biomarkers of psychiatric disease susceptibility.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37431265,

title = {Relationship between insulin and Netrin-1/DCC guidance cue pathway regulation in the prefrontal cortex of rodents exposed to prenatal dietary restriction},

author = {Aashita Batra and Santiago Cuesta and Marcio Bonesso Alves and Jose Maria Restrepo and Michel Giroux and Daniela Pereira Laureano and Amanda Brondani Mucellini Lovato and Patrícia Maidana Miguel and Tania Diniz Machado and Roberta Dalle Molle and Cecilia Flores and Patricia Pelufo Silveira},

doi = {10.1017/S204017442300017X},

issn = {2040-1752},

year  = {2023},

date = {2023-07-01},

journal = {J Dev Orig Health Dis},

pages = {1--7},

abstract = {Fetal restriction (FR) alters insulin sensitivity, but it is unknown how the metabolic profile associated with restriction affects development of the dopamine (DA) system and DA-related behaviors. The Netrin-1/DCC guidance cue system participates in maturation of the mesocorticolimbic DA circuitry. Therefore, our objective was to identify if FR modifies Netrin-1/DCC receptor protein expression in the prefrontal cortex (PFC) at birth and mRNA in adulthood in rodent males. We used cultured HEK293 cells to assess if levels of miR-218, microRNA regulator of DCC, are sensitive to insulin. To assess this, pregnant dams were subjected to a 50% FR diet from gestational day 10 until birth. Medial PFC (mPFC) DCC/Netrin-1 protein expression was measured at P0 at baseline and /-1 mRNA levels were quantified in adults 15 min after a saline/insulin injection. miR-218 levels in HEK-293 cells were measured in response to insulin exposure. At P0, Netrin-1 levels are downregulated in FR animals in comparison to controls. In adult rodents, insulin administration results in an increase in  mRNA levels in control but not FR rats. In HEK293 cells, there is a positive correlation between insulin concentration and miR-218 levels. Since miR-218 is a  gene expression regulator and our in vitro results show that insulin regulates miR-218 levels, we suggest that FR-induced changes in insulin sensitivity could be affecting  expression via miR-218, impacting DA system maturation and organization. As fetal adversity is linked to nonadaptive behaviors later in life, this may contribute to early identification of vulnerability to chronic diseases associated with fetal adversity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37406925,

title = {A Glucocorticoid-Sensitive Hippocampal Gene Network Moderates the Impact of Early-Life Adversity on Mental Health Outcomes},

author = {Danusa Mar Arcego and Jan-Paul Buschdorf and Nicholas O'Toole and Zihan Wang and Barbara Barth and Irina Pokhvisneva and Nirmala Arul Rayan and Sachin Patel and Euclides José de Mendonça Filho and Patrick Lee and Jennifer Tan and Ming Xuan Koh and Chu Ming Sim and Carine Parent and Randriely Merscher Sobreira de Lima and Andrew Clappison and Kieran J O'Donnell and Carla Dalmaz and Janine Arloth and Nadine Provençal and Elisabeth B Binder and Josie Diorio and Patrícia Pelufo Silveira and Michael J Meaney},

doi = {10.1016/j.biopsych.2023.06.028},

issn = {1873-2402},

year  = {2023},

date = {2023-07-01},

journal = {Biol Psychiatry},

abstract = {BACKGROUND: Early stress increases the risk for psychiatric disorders. Glucocorticoids are stress mediators that regulate transcriptional activity and morphology in the hippocampus, which is implicated in the pathophysiology of multiple psychiatric conditions. We aimed to establish the relevance of hippocampal, glucocorticoid-induced transcriptional activity as a mediator of the effects of early life on later psychopathology in humans.nnMETHODS: RNA sequencing was performed with anterior and posterior hippocampal dentate gyrus from adult female macaques (n = 12/group) that were chronically treated with betamethasone (glucocorticoid receptor agonist) or vehicle. Coexpression network analysis identified a preserved gene network in the posterior hippocampal dentate gyrus that was strongly associated with glucocorticoid exposure. The single nucleotide polymorphisms in the genes in this network were used to create an expression-based polygenic score in humans.nnRESULTS: The expression-based polygenic score significantly moderated the association between early adversity and psychotic disorders in adulthood (UK Biobank, women, n = 44,519) and on child peer relations (ALSPAC [Avon Longitudinal Study of Parents and Children], girls, n = 1666 for 9-year-olds and n = 1594 for 11-year-olds), an endophenotype for later psychosis. Analyses revealed that this network was enriched for glucocorticoid-induced epigenetic remodeling in human hippocampal cells. We also found a significant association between single nucleotide polymorphisms from the expression-based polygenic score and adult brain gray matter density.nnCONCLUSIONS: We provide an approach for the use of transcriptomic data from animal models together with human data to study the impact of environmental influences on mental health. The results are consistent with the hypothesis that hippocampal glucocorticoid-related transcriptional activity mediates the effects of early adversity on neural mechanisms implicated in psychiatric disorders.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37002151,

title = {New Research Perspectives on the Interplay Between Genes and Environment on Executive Function Development},

author = {Patrícia Maidana Miguel and Michael J Meaney and Patrícia Pelufo Silveira},

doi = {10.1016/j.biopsych.2023.01.008},

issn = {1873-2402},

year  = {2023},

date = {2023-07-01},

journal = {Biol Psychiatry},

volume = {94},

number = {2},

pages = {131--141},

abstract = {Executive functions (EFs) are a set of skills responsible for the cognitive control of emotional states and behavior as well as for information processing required for learning and memory. Impairments in these abilities, such as focused attention, working memory, cognitive flexibility, and self-regulation, are implicated in a variety of psychopathologies across the lifespan. EF development shows a protracted course that begins in early childhood and continues throughout adolescence and into early adulthood. Maturation of EFs is subject to environmental influences such that adversity during development can affect multiple EF-mediated processes and outcomes. In this review, we describe sensitive periods for the development of EFs and the effects of adverse environmental exposures, with consideration of the underlying neurobiological mechanisms. However, there is considerable interindividual variation in the impact of adversity, with some individuals more vulnerable and some more resilient to its effects. We explore the evidence for the genetic contribution to interindividual variation in EFs, providing an overview of classic studies, followed by the results of recent genome-wide association studies and innovative genomic methods. Finally, we review studies investigating the interdependence between early-life adversities and genetic factors on EFs. We discuss the importance of novel functional genomics approaches, multilevel analyses, and big data to elucidate the complexity of the relationships between genes, environment, and the development of EFs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37142650,

title = {Omega-3 polygenic score protects against altered eating behavior in intrauterine growth-restricted children},

author = {Angela M Jaramillo-Ospina and Gabriel T Roman and Danitsa M Rodrigues and Sachin Patel and Irina Pokhvisneva and Valentina G Chakr and Robert D Levitan and Michael J Meaney and Patricia P Silveira},

doi = {10.1038/s41390-023-02609-y},

issn = {1530-0447},

year  = {2023},

date = {2023-05-01},

journal = {Pediatr Res},

abstract = {BACKGROUND: Alterations in eating behavior are common in infants with intrauterine growth restriction (IUGR); omega-3 polyunsaturated fatty acids (PUFA) could provide protection. We hypothesized that those born IUGR with a genetic background associated with increased production of omega-3-PUFA will have more adaptive eating behaviors during childhood.nnMETHODS: IUGR/non-IUGR classified infants from MAVAN and GUSTO cohorts were included at the age of 4 and 5 years, respectively. Their parents reported child's eating behaviors using the child eating behavior questionnaire-CEBQ. Based on the GWAS on serum PUFA (Coltell 2020), three polygenic scores were calculated.nnRESULTS: Significant interactions between IUGR and polygenic score for omega-3-PUFA on emotional overeating (β = -0.15, P = 0.049 GUSTO) and between IUGR and polygenic score for omega-6/omega-3-PUFA on desire to drink (β = 0.35, P = 0.044 MAVAN), pro-intake/anti-intake ratio (β = 0.10, P = 0.042 MAVAN), and emotional overeating (β = 0.16, P = 0.043 GUSTO) were found. Only in IUGR, a higher polygenic score for omega-3-PUFA associated with lower emotional overeating, while a higher polygenic score for omega-6/omega-3-PUFA ratio was associated with a higher desire to drink, emotional overeating, and pro-intake/anti-intake.nnCONCLUSION: Only in IUGR, the genetic background for higher omega-3-PUFA is associated with protection against altered eating behavior, while the genetic score for a higher omega-6/omega-3-PUFA ratio is associated with altered eating behavior.nnIMPACT: A genetic background related to a higher polygenic score for omega-3 PUFA protected infants born IUGR against eating behavior alterations, while a higher polygenic score for omega-6/omega-3 PUFA ratio increased the risk of having eating behavior alterations only in infants born IUGR, irrespective of their adiposity in childhood. Genetic individual differences modify the effect of being born IUGR on eating outcomes, increasing the vulnerability/resilience to eating disorders in IUGR group and likely contributing to their risk for developing metabolic diseases later in life.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37143480,

title = {Household Social Needs, Emotional Functioning, and Stress in Low-Income Latinx Children and their Mothers},

author = {Victoria F Keeton and Janice F Bell and Christiana Drake and Erik O Fernandez Y Garcia and Matthew Pantell and Danielle Hessler and Holly Wing and Patricia P Silveira and Kieran J O'Donnell and Euclides José de Mendonça Filho and Michael J Meaney and Laura M Gottlieb},

doi = {10.1007/s10826-023-02532-0},

issn = {1062-1024},

year  = {2023},

date = {2023-03-01},

journal = {J Child Fam Stud},

volume = {32},

number = {3},

pages = {796--811},

abstract = {Latinx families may be particularly vulnerable to emotional dysfunction, due to higher rates of economic hardship and complex social influences in this population. Little is known about the impact of environmental stressors such as unmet social needs and maternal stress on the emotional health of Latinx children from low-income families. We conducted secondary analyses using survey and biomarker data from 432 Latinx children and mothers collected in a separate study. We used binomial and multinomial logistic regression to test if household social needs, or maternal perceived stress or hair cortisol concentration (HCC), predicted child measures of emotional functioning or child HCC, independent of relevant sociodemographic factors. Approximately 40% of children in the sample had symptoms consistent with emotional dysfunction, and over 37% of households reported five or more social needs. High perceived maternal stress predicted higher odds of child emotional dysfunction (OR = 2.15; 95% CI [1.14, 4.04]; p = 0.01), and high maternal HCC was positively associated with high child HCC (OR = 10.60; 95% CI [4.20, 26.74]; p < 0.01). Most individual household social needs, as well as the level of household social need, were not independently associated with child emotional dysfunction or child HCC. Our findings begin to define a framework for understanding emotional health, stress, and resilience when caring for Latinx children and mothers living with high levels of social need, and the need for integrated mental health and social needs screening and interventions in settings that serve this population.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36690304,

title = {Examining the biological mechanisms of human mental disorders resulting from gene-environment interdependence using novel functional genomic approaches},

author = {Patrícia Pelufo Silveira and Michael J Meaney},

doi = {10.1016/j.nbd.2023.106008},

issn = {1095-953X},

year  = {2023},

date = {2023-03-01},

journal = {Neurobiol Dis},

volume = {178},

pages = {106008},

abstract = {We explore how functional genomics approaches that integrate datasets from human and non-human model systems can improve our understanding of the effect of gene-environment interplay on the risk for mental disorders. We start by briefly defining the G-E paradigm and its challenges and then discuss the different levels of regulation of gene expression and the corresponding data existing in humans (genome wide genotyping, transcriptomics, DNA methylation, chromatin modifications, chromosome conformational changes, non-coding RNAs, proteomics and metabolomics), discussing novel approaches to the application of these data in the study of the origins of mental health. Finally, we discuss the multilevel integration of diverse types of data. Advance in the use of functional genomics in the context of a G-E perspective improves the detection of vulnerabilities, informing the development of preventive and therapeutic interventions.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36750733,

title = {A sex-specific genome-wide association study of depression phenotypes in UK Biobank},

author = {Patrícia Pelufo Silveira and Irina Pokhvisneva and David M Howard and Michael J Meaney},

doi = {10.1038/s41380-023-01960-0},

issn = {1476-5578},

year  = {2023},

date = {2023-02-01},

journal = {Mol Psychiatry},

abstract = {There are marked sex differences in the prevalence, phenotypic presentation and treatment response for major depression. While genome-wide association studies (GWAS) adjust for sex differences, to date, no studies seek to identify sex-specific markers and pathways. In this study, we performed a sex-stratified genome-wide association analysis for broad depression with the UK Biobank total participants (N = 274,141), including only non-related participants, as well as with males (N = 127,867) and females (N = 146,274) separately. Bioinformatics analyses were performed to characterize common and sex-specific markers and associated processes/pathways. We identified 11 loci passing genome-level significance (P < 5 × 10) in females and one in males. In both males and females, genetic correlations were significant between the broad depression GWA and other psychopathologies; however, correlations with educational attainment and metabolic features including body fat, waist circumference, waist-to-hip ratio and triglycerides were significant only in females. Gene-based analysis showed 147 genes significantly associated with broad depression in the total sample, 64 in the females and 53 in the males. Gene-based analysis revealed "Regulation of Gene Expression" as a common biological process, but suggested sex-specific molecular mechanisms. Finally, sex-specific polygenic risk scores (PRSs) for broad depression outperformed total and the opposite sex PRSs in the prediction of broad major depressive disorder. These findings provide evidence for sex-dependent genetic pathways for clinical depression as well as for health conditions comorbid with depression.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37534032,

title = {Development of risk prediction models for depression combining genetic and early life risk factors},

author = {Tianyuan Lu and Patrícia Pelufo Silveira and Celia M T Greenwood},

doi = {10.3389/fnins.2023.1143496},

issn = {1662-4548},

year  = {2023},

date = {2023-01-01},

journal = {Front Neurosci},

volume = {17},

pages = {1143496},

abstract = {BACKGROUND: Both genetic and early life risk factors play important roles in the pathogenesis and progression of adult depression. However, the interplay between these risk factors and their added value to risk prediction models have not been fully elucidated.nnMETHODS: Leveraging a meta-analysis of major depressive disorder genome-wide association studies ( = 45,591 cases and 97,674 controls), we developed and optimized a polygenic risk score for depression using LDpred in a model selection dataset from the UK Biobank ( = 130,092 European ancestry individuals). In a UK Biobank test dataset ( = 278,730 European ancestry individuals), we tested whether the polygenic risk score and early life risk factors were associated with each other and compared their associations with depression phenotypes. Finally, we conducted joint predictive modeling to combine this polygenic risk score with early life risk factors by stepwise regression, and assessed the model performance in identifying individuals at high risk of depression.nnRESULTS: In the UK Biobank test dataset, the polygenic risk score for depression was moderately associated with multiple early life risk factors. For instance, a one standard deviation increase in the polygenic risk score was associated with 1.16-fold increased odds of frequent domestic violence (95% CI: 1.14-1.19) and 1.09-fold increased odds of not having access to medical care as a child (95% CI: 1.05-1.14). However, the polygenic risk score was more strongly associated with depression phenotypes than most early life risk factors. A joint predictive model integrating the polygenic risk score, early life risk factors, age and sex achieved an AUROC of 0.6766 for predicting strictly defined major depressive disorder, while a model without the polygenic risk score and a model without any early life risk factors had an AUROC of 0.6593 and 0.6318, respectively.nnCONCLUSION: We have developed a polygenic risk score to partly capture the genetic liability to depression. Although genetic and early life risk factors can be correlated, joint predictive models improved risk stratification despite limited improvement in magnitude, and may be explored as tools to better identify individuals at high risk of depression.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37008220,

title = {Examining resting-state network connectivity in children exposed to perinatal maternal adversity using anatomically weighted functional connectivity (awFC) analyses; A preliminary report},

author = {Sondos Ayyash and Aleeza Sunderji and Heather D Gallant and Alexander Hall and Andrew D Davis and Irina Pokhvisneva and Michael J Meaney and Patricia Pelufo Silveira and Roberto B Sassi and Geoffrey B Hall},

doi = {10.3389/fnins.2023.1066373},

issn = {1662-4548},

year  = {2023},

date = {2023-01-01},

journal = {Front Neurosci},

volume = {17},

pages = {1066373},

abstract = {INTRODUCTION: Environmental perturbations during critical periods can have pervasive, organizational effects on neurodevelopment. To date, the literature examining the long-term impact of early life adversity has largely investigated structural and functional imaging data outcomes independently. However, emerging research points to a relationship between functional connectivity and the brain's underlying structural architecture. For instance, functional connectivity can be mediated by the presence of direct or indirect anatomical pathways. Such evidence warrants the use of structural and functional imaging in tandem to study network maturation. Accordingly, this study examines the impact of poor maternal mental health and socioeconomic context during the perinatal period on network connectivity in middle childhood using an anatomically weighted functional connectivity (awFC) approach. awFC is a statistical model that identifies neural networks by incorporating information from both structural and functional imaging data.nnMETHODS: Resting-state fMRI and DTI scans were acquired from children aged 7-9 years old.nnRESULTS: Our results indicate that maternal adversity during the perinatal period can affect offspring's resting-state network connectivity during middle childhood. Specifically, in comparison to controls, children of mothers who had poor perinatal maternal mental health and/or low socioeconomic status exhibited greater awFC in the ventral attention network.nnDISCUSSION: These group differences were discussed in terms of the role this network plays in attention processing and maturational changes that may accompany the consolidation of a more adult-like functional cortical organization. Furthermore, our results suggest that there is value in using an awFC approach as it may be more sensitive in highlighting connectivity differences in developmental networks associated with higher-order cognitive and emotional processing, as compared to stand-alone FC or SC analyses.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36650307,

title = {Linking specific biological signatures to different childhood adversities: findings from the HERO project},

author = {Euclides José de Mendonça Filho and Irina Pokhvisneva and Christina Maria Maalouf and Carine Parent and Shanna B Mliner and Natalie Slopen and David R Williams and Nicole R Bush and William Thomas Boyce and Pat Levitt and Charles A Nelson and Megan R Gunnar and Michael J Meaney and Jack P Shonkoff and Patricia Pelufo Silveira and },

doi = {10.1038/s41390-022-02415-y},

issn = {1530-0447},

year  = {2023},

date = {2023-01-01},

journal = {Pediatr Res},

abstract = {BACKGROUND: Although investigations have begun to differentiate biological and neurobiological responses to a variety of adversities, studies considering both endocrine and immune function in the same datasets are limited.nnMETHODS: Associations between proximal (family functioning, caregiver depression, and anxiety) and distal (SES-D; socioeconomic disadvantage) early-life adversities with salivary inflammatory biomarkers (IL-1β, IL-6, IL-8, and TNF-α) and hair HPA markers (cortisol, cortisone, and dehydroepiandrosterone) were examined in two samples of young U.S. children (N = 142; N = 145).nnRESULTS: Children exposed to higher SES-D had higher levels of TNF-α (B = 0.13, p = 0.011), IL-1β (B = 0.10, p = 0.033), and DHEA (B = 0.16, p = 0.011). Higher family dysfunction was associated with higher cortisol (B = 0.08, p = 0.033) and cortisone (B = 0.05, p = 0.003). An interaction between SES-D and family dysfunction was observed for cortisol levels (p = 0.020) whereby children exposed to lower/average levels of SES-D exhibited a positive association between family dysfunction and cortisol levels, whereas children exposed to high levels of SES-D did not. These findings were partially replicated in the second sample.nnCONCLUSIONS: Our results indicate that these biological response systems may react differently to different forms of early-life adversity.nnIMPACT: Different forms of early-life adversity have varied stress signatures, and investigations of early-life adversities with inflammation and HPA markers are lacking. Children with higher socioeconomic disadvantage had higher TNF-α, IL-1β, and DHEA. Higher family dysfunction was associated with higher hair cortisol and cortisone levels, and the association between family dysfunction and cortisol was moderated by socioeconomic disadvantage. Biological response systems (immune and endocrine) were differentially associated with distinct forms of early-life adversities.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}