Rene Olvera - Academia.edu (original) (raw)

Papers by Rene Olvera

European Neuropsychopharmacology

European Neuropsychopharmacology

Journal of Affective Disorders

Human Brain Mapping

White matter microstructure is affected by immune system activity via the actions of circulating ... more White matter microstructure is affected by immune system activity via the actions of circulating pro-inflammatory cytokines. Although white matter microstructure and inflammatory measures are significantly heritable, it is unclear if overlapping genetic factors influence these traits in humans. We conducted genetic correlation analyses of these traits using randomly ascertained extended pedigrees from the Genetics of Brain Structure and Function Study (N = 1862, 59% females, ages 18-97 years; 42 ± 15.7). White matter microstructure was assessed using fractional anisotropy (FA) calculated from diffusion tensor imaging (DTI). Circulating levels (pg/mL) of proinflammatory cytokines (IL-6, IL-8, and TNFα) phenotypically associated with white matter microstructure were quantified from blood serum. All traits were significantly heritable (h 2 ranging from 0.41 to 0.66 for DTI measures and from 0.18 to 0.30 for inflammatory markers). Phenotypically, higher levels of circulating inflammatory markers were associated with lower FA values across the brain (r = −.03 to r = −.17).

European Neuropsychopharmacology

Journal of the American Academy of Child and Adolescent Psychiatry, 2018

Early alcohol use initiation predicts onset of alcohol use disorders in adulthood. However, littl... more Early alcohol use initiation predicts onset of alcohol use disorders in adulthood. However, little is known about developmental trajectories of alcohol use initiation and their putative biological and environmental correlates. Adolescents (N = 330) with high or low familial loading for depression were assessed annually for up to 6 years. Data were collected assessing affective symptoms, alcohol use, and stress at each assessment. Adolescents also participated in a functional magnetic resonance imaging protocol that included measurement of threat-related amygdala and reward-related ventral striatum activity. Latent class analyses identified 2 trajectories of alcohol use initiation. Early initiators (n = 32) reported greater baseline alcohol use and rate of change of use compared with late initiators and/or current abstainers (n = 298). Early initiators reported higher baseline levels of stressful life events (p = .001) and exhibited higher amygdala (p = .001) but not ventral striatum...

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, Jan 23, 2018

Suicide is major public health concern; one million individuals worldwide die by suicide each yea... more Suicide is major public health concern; one million individuals worldwide die by suicide each year of which there are many more attempts. Thus, it is imperative that robust and reliable indicators, or biomarkers, of suicide risk be identified so that individuals at risk can be identified and provided appropriate interventions as quickly as possible. Previous work has revealed a relationship between low levels of circulating cholesterol and suicide risk, implicating cholesterol level as one such potential biomarker, but the factors underlying this relationship remain unknown. In the present study, we applied a combination of bivariate polygenic and coefficient-of-relatedness analysis, followed by mediation analysis, in a large sample of Mexican-American individuals from extended pedigrees [N = 1897; 96 pedigrees (average size = 19.17 individuals, range = 2-189) 60% female; mean age = 42.58 years, range = 18-97 years, sd = 15.75 years] with no exclusion criteria for any given psychiat...

Journal of affective disorders, Jul 1, 2018

Immune system abnormalities have been repeatedly observed in several psychiatric disorders, inclu... more Immune system abnormalities have been repeatedly observed in several psychiatric disorders, including severe depression and anxiety. However, whether specific immune mediators play an early role in the etiopathogenesis of these disorders remains unknown. In a longitudinal design, component-wise gradient boosting was used to build models of depression, assessed by the Mood-Feelings Questionnaire-Child (MFQC), and anxiety, assessed by the Screen for Child Anxiety Related Emotional Disorders (SCARED) in 254 adolescents from a large set of candidate predictors, including sex, race, 39 inflammatory proteins, and the interactions between those proteins and time. Each model was reduced via backward elimination to maximize parsimony and generalizability. Component-wise gradient boosting and model reduction found that female sex, growth- regulated oncogene (GRO), and transforming growth factor alpha (TGF-alpha) predicted depression, while female sex predicted anxiety. Differential onset of p...

Cerebral cortex (New York, N.Y. : 1991), Jan 28, 2017

The cerebral cortex may be organized into anatomical genetic modules, communities of brain region... more The cerebral cortex may be organized into anatomical genetic modules, communities of brain regions with shared genetic influences via pleiotropy. Such modules could represent novel phenotypes amenable to large-scale gene discovery. This modular structure was investigated with network analysis of in vivo MRI of extended pedigrees, revealing a "multiscale" structure where smaller and larger modules exist simultaneously and in partially overlapping fashion across spatial scales, in contrast to prior work suggesting a specific number of cortical thickness modules. Inter-regional genetic correlations, gene co-expression patterns and computational models indicate that two simple organizational principles account for a large proportion of the apparent complexity in the network of genetic correlations. First, regions are strongly genetically correlated with their homologs in the opposite cerebral hemisphere. Second, regions are strongly genetically correlated with nearby regions i...

European Neuropsychopharmacology

European Neuropsychopharmacology

European Neuropsychopharmacology

Background:The lipidome is rapidly garnering interest in the field of psychiatry. Recent studies ... more Background:The lipidome is rapidly garnering interest in the field of psychiatry. Recent studies have implicated lipidomic changes across numerous psychiatric disorders. In particular, there is growing evidence that the concentrations of several classes of lipids are altered in those diagnosed with MDD. However, for lipidomic abnormalities to be considered potential treatment targets for MDD (rather than secondary manifestations of the disease), a shared etiology between lipid concentrations and MDD should be demonstrated.Methods:In a sample of 567 individuals from 37 extended pedigrees (average size 13.57 people, range = 3–80), we used mass spectrometry lipidomic measures to evaluate the genetic overlap between twenty-three biologically distinct lipid classes and a dimensional scale of MDD.Results:We found that the lipid class with the largest endophenotype ranking value (ERV, a standardized parametric measure of pleiotropy) were ether-phosphodatidylcholines (alkylphosphatidylcholine, PC(O) and alkenylphosphatidylcholine, PC(P) subclasses). Furthermore, we examined the cluster structure of the twenty-five species within the top-ranked lipid class, and the relationship of those clusters with MDD. This analysis revealed that species containing arachidonic acid generally exhibited the greatest degree of genetic overlap with MDD.Conclusions:This study is the first to demonstrate a shared genetic etiology between MDD and ether-phosphatidylcholine species containing arachidonic acid, an omega-6 fatty acid that is a precursor to inflammatory mediators, such as prostaglandins. The study highlights the potential utility of the well-characterized linoleic/arachidonic acid inflammation pathway as a diagnostic marker and/or treatment target for MDD.

Journal of adolescence, Dec 1, 2016

Adolescents with Attention Deficit Hyperactivity Disorder (ADHD) and Conduct Disorder (CD) experi... more Adolescents with Attention Deficit Hyperactivity Disorder (ADHD) and Conduct Disorder (CD) experience deficits in neuropsychological measures of attention, inhibition, and reward processes. Methylphenidate treatment for ADHD and CD has acute effects on these processes. Some of these same aspects of performance are separately described in the Behavioral Model of Impulsivity, which uses a modified approach to measurement. This study characterized the acute effects of methylphenidate attention, initiation, inhibition, and reward processes described in this model of impulsivity. Thirty-one adolescents from the United States of America with comorbid ADHD and CD completed measures of impulsivity (response initiation, response inhibition, and consequence) and attention following placebo, 20 mg, and 40 mg of a long-acting dose of methylphenidate. Methylphenidate effects on attentional performance was more robust than on any of the measures of impulsivity. Adolescent performance from this be...

The Journal of neuroscience : the official journal of the Society for Neuroscience, May 3, 2017

The accurate estimation of age using methylation data has proved a useful and heritable biomarker... more The accurate estimation of age using methylation data has proved a useful and heritable biomarker, with acceleration in epigenetic age predicting a number of age-related phenotypes. Measures of white matter integrity in the brain are also heritable and highly sensitive to both normal and pathological aging processes across adulthood. We consider the phenotypic and genetic interrelationships between epigenetic age acceleration and white matter integrity in humans. Our goal was to investigate processes that underlie interindividual variability in age-related changes in the brain. Using blood taken from a Mexican-American extended pedigree sample (n = 628; age = 23.28-93.11 years), epigenetic age was estimated using the method developed by Horvath (2013). For n = 376 individuals, diffusion tensor imaging scans were also available. The interrelationship between epigenetic age acceleration and global white matter integrity was investigated with variance decomposition methods. To test for...

Susceptibility genes for psychiatric and neurological disorders - including APOE, BDNF, CLU, CNTN... more Susceptibility genes for psychiatric and neurological disorders - including APOE, BDNF, CLU, CNTNAP2, COMT, DISC1, DTNBP1, ErbB4, HFE, NRG1, NTKR3, and ZNF804A - have been reported to affect white matter (WM) microstructure in the healthy human brain, as assessed through diffusion tensor imaging (DTI). However, effects of single nucleotide polymorphisms (SNPs) in these genes explain only a small fraction of the overall variance and are challenging to detect reliably in single cohort studies. To date, few studies have evaluated the reproducibility of these results. As part of the ENIGMA-DTI consortium, we pooled regional fractional anisotropy (FA) measures for 6,165 subjects (CEU ancestry N=4,458) from 11 cohorts worldwide to evaluate effects of 15 candidate SNPs by examining their associations with WM microstructure. Additive association tests were conducted for each SNP. We used several meta-analytic and mega-analytic designs, and we evaluated regions of interest at multiple granul...

Bipolar disorders, Mar 23, 2017

Individuals with bipolar disorder (BPD) exhibit alterations in their phospholipid levels. It is u... more Individuals with bipolar disorder (BPD) exhibit alterations in their phospholipid levels. It is unclear whether these alterations are a secondary consequence of illness state, or if phospholipids and illness risk overlap genetically. If the latter were true, then phospholipids might provide key insights into the pathophysiology of the illness. Therefore, we rank-ordered phospholipid classes by their genetic overlap with BPD risk in order to establish which class might be most informative in terms of increasing our understanding of illness pathophysiology. Analyses were conducted in a sample of 558 individuals, unselected for BPD, from 38 extended pedigrees (average family size=14.79, range=2-82). We calculated a coefficient of relatedness for all family members of nine individuals with BPD in the sample (N=185); this coefficient was set to be zero in unrelated individuals (N=373). Then, under an endophenotype ranking value (ERV) approach, this scalar index was tested against 13 seru...

Nature communications, Jan 18, 2017

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial na... more The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for…

European Neuropsychopharmacology

European Neuropsychopharmacology

Journal of Affective Disorders

Human Brain Mapping

White matter microstructure is affected by immune system activity via the actions of circulating ... more White matter microstructure is affected by immune system activity via the actions of circulating pro-inflammatory cytokines. Although white matter microstructure and inflammatory measures are significantly heritable, it is unclear if overlapping genetic factors influence these traits in humans. We conducted genetic correlation analyses of these traits using randomly ascertained extended pedigrees from the Genetics of Brain Structure and Function Study (N = 1862, 59% females, ages 18-97 years; 42 ± 15.7). White matter microstructure was assessed using fractional anisotropy (FA) calculated from diffusion tensor imaging (DTI). Circulating levels (pg/mL) of proinflammatory cytokines (IL-6, IL-8, and TNFα) phenotypically associated with white matter microstructure were quantified from blood serum. All traits were significantly heritable (h 2 ranging from 0.41 to 0.66 for DTI measures and from 0.18 to 0.30 for inflammatory markers). Phenotypically, higher levels of circulating inflammatory markers were associated with lower FA values across the brain (r = −.03 to r = −.17).

European Neuropsychopharmacology

Journal of the American Academy of Child and Adolescent Psychiatry, 2018

Early alcohol use initiation predicts onset of alcohol use disorders in adulthood. However, littl... more Early alcohol use initiation predicts onset of alcohol use disorders in adulthood. However, little is known about developmental trajectories of alcohol use initiation and their putative biological and environmental correlates. Adolescents (N = 330) with high or low familial loading for depression were assessed annually for up to 6 years. Data were collected assessing affective symptoms, alcohol use, and stress at each assessment. Adolescents also participated in a functional magnetic resonance imaging protocol that included measurement of threat-related amygdala and reward-related ventral striatum activity. Latent class analyses identified 2 trajectories of alcohol use initiation. Early initiators (n = 32) reported greater baseline alcohol use and rate of change of use compared with late initiators and/or current abstainers (n = 298). Early initiators reported higher baseline levels of stressful life events (p = .001) and exhibited higher amygdala (p = .001) but not ventral striatum...

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, Jan 23, 2018

Suicide is major public health concern; one million individuals worldwide die by suicide each yea... more Suicide is major public health concern; one million individuals worldwide die by suicide each year of which there are many more attempts. Thus, it is imperative that robust and reliable indicators, or biomarkers, of suicide risk be identified so that individuals at risk can be identified and provided appropriate interventions as quickly as possible. Previous work has revealed a relationship between low levels of circulating cholesterol and suicide risk, implicating cholesterol level as one such potential biomarker, but the factors underlying this relationship remain unknown. In the present study, we applied a combination of bivariate polygenic and coefficient-of-relatedness analysis, followed by mediation analysis, in a large sample of Mexican-American individuals from extended pedigrees [N = 1897; 96 pedigrees (average size = 19.17 individuals, range = 2-189) 60% female; mean age = 42.58 years, range = 18-97 years, sd = 15.75 years] with no exclusion criteria for any given psychiat...

Journal of affective disorders, Jul 1, 2018

Immune system abnormalities have been repeatedly observed in several psychiatric disorders, inclu... more Immune system abnormalities have been repeatedly observed in several psychiatric disorders, including severe depression and anxiety. However, whether specific immune mediators play an early role in the etiopathogenesis of these disorders remains unknown. In a longitudinal design, component-wise gradient boosting was used to build models of depression, assessed by the Mood-Feelings Questionnaire-Child (MFQC), and anxiety, assessed by the Screen for Child Anxiety Related Emotional Disorders (SCARED) in 254 adolescents from a large set of candidate predictors, including sex, race, 39 inflammatory proteins, and the interactions between those proteins and time. Each model was reduced via backward elimination to maximize parsimony and generalizability. Component-wise gradient boosting and model reduction found that female sex, growth- regulated oncogene (GRO), and transforming growth factor alpha (TGF-alpha) predicted depression, while female sex predicted anxiety. Differential onset of p...

Cerebral cortex (New York, N.Y. : 1991), Jan 28, 2017

The cerebral cortex may be organized into anatomical genetic modules, communities of brain region... more The cerebral cortex may be organized into anatomical genetic modules, communities of brain regions with shared genetic influences via pleiotropy. Such modules could represent novel phenotypes amenable to large-scale gene discovery. This modular structure was investigated with network analysis of in vivo MRI of extended pedigrees, revealing a "multiscale" structure where smaller and larger modules exist simultaneously and in partially overlapping fashion across spatial scales, in contrast to prior work suggesting a specific number of cortical thickness modules. Inter-regional genetic correlations, gene co-expression patterns and computational models indicate that two simple organizational principles account for a large proportion of the apparent complexity in the network of genetic correlations. First, regions are strongly genetically correlated with their homologs in the opposite cerebral hemisphere. Second, regions are strongly genetically correlated with nearby regions i...

European Neuropsychopharmacology

European Neuropsychopharmacology

European Neuropsychopharmacology

Background:The lipidome is rapidly garnering interest in the field of psychiatry. Recent studies ... more Background:The lipidome is rapidly garnering interest in the field of psychiatry. Recent studies have implicated lipidomic changes across numerous psychiatric disorders. In particular, there is growing evidence that the concentrations of several classes of lipids are altered in those diagnosed with MDD. However, for lipidomic abnormalities to be considered potential treatment targets for MDD (rather than secondary manifestations of the disease), a shared etiology between lipid concentrations and MDD should be demonstrated.Methods:In a sample of 567 individuals from 37 extended pedigrees (average size 13.57 people, range = 3–80), we used mass spectrometry lipidomic measures to evaluate the genetic overlap between twenty-three biologically distinct lipid classes and a dimensional scale of MDD.Results:We found that the lipid class with the largest endophenotype ranking value (ERV, a standardized parametric measure of pleiotropy) were ether-phosphodatidylcholines (alkylphosphatidylcholine, PC(O) and alkenylphosphatidylcholine, PC(P) subclasses). Furthermore, we examined the cluster structure of the twenty-five species within the top-ranked lipid class, and the relationship of those clusters with MDD. This analysis revealed that species containing arachidonic acid generally exhibited the greatest degree of genetic overlap with MDD.Conclusions:This study is the first to demonstrate a shared genetic etiology between MDD and ether-phosphatidylcholine species containing arachidonic acid, an omega-6 fatty acid that is a precursor to inflammatory mediators, such as prostaglandins. The study highlights the potential utility of the well-characterized linoleic/arachidonic acid inflammation pathway as a diagnostic marker and/or treatment target for MDD.

Journal of adolescence, Dec 1, 2016

Adolescents with Attention Deficit Hyperactivity Disorder (ADHD) and Conduct Disorder (CD) experi... more Adolescents with Attention Deficit Hyperactivity Disorder (ADHD) and Conduct Disorder (CD) experience deficits in neuropsychological measures of attention, inhibition, and reward processes. Methylphenidate treatment for ADHD and CD has acute effects on these processes. Some of these same aspects of performance are separately described in the Behavioral Model of Impulsivity, which uses a modified approach to measurement. This study characterized the acute effects of methylphenidate attention, initiation, inhibition, and reward processes described in this model of impulsivity. Thirty-one adolescents from the United States of America with comorbid ADHD and CD completed measures of impulsivity (response initiation, response inhibition, and consequence) and attention following placebo, 20 mg, and 40 mg of a long-acting dose of methylphenidate. Methylphenidate effects on attentional performance was more robust than on any of the measures of impulsivity. Adolescent performance from this be...

The Journal of neuroscience : the official journal of the Society for Neuroscience, May 3, 2017

The accurate estimation of age using methylation data has proved a useful and heritable biomarker... more The accurate estimation of age using methylation data has proved a useful and heritable biomarker, with acceleration in epigenetic age predicting a number of age-related phenotypes. Measures of white matter integrity in the brain are also heritable and highly sensitive to both normal and pathological aging processes across adulthood. We consider the phenotypic and genetic interrelationships between epigenetic age acceleration and white matter integrity in humans. Our goal was to investigate processes that underlie interindividual variability in age-related changes in the brain. Using blood taken from a Mexican-American extended pedigree sample (n = 628; age = 23.28-93.11 years), epigenetic age was estimated using the method developed by Horvath (2013). For n = 376 individuals, diffusion tensor imaging scans were also available. The interrelationship between epigenetic age acceleration and global white matter integrity was investigated with variance decomposition methods. To test for...

Susceptibility genes for psychiatric and neurological disorders - including APOE, BDNF, CLU, CNTN... more Susceptibility genes for psychiatric and neurological disorders - including APOE, BDNF, CLU, CNTNAP2, COMT, DISC1, DTNBP1, ErbB4, HFE, NRG1, NTKR3, and ZNF804A - have been reported to affect white matter (WM) microstructure in the healthy human brain, as assessed through diffusion tensor imaging (DTI). However, effects of single nucleotide polymorphisms (SNPs) in these genes explain only a small fraction of the overall variance and are challenging to detect reliably in single cohort studies. To date, few studies have evaluated the reproducibility of these results. As part of the ENIGMA-DTI consortium, we pooled regional fractional anisotropy (FA) measures for 6,165 subjects (CEU ancestry N=4,458) from 11 cohorts worldwide to evaluate effects of 15 candidate SNPs by examining their associations with WM microstructure. Additive association tests were conducted for each SNP. We used several meta-analytic and mega-analytic designs, and we evaluated regions of interest at multiple granul...

Bipolar disorders, Mar 23, 2017

Individuals with bipolar disorder (BPD) exhibit alterations in their phospholipid levels. It is u... more Individuals with bipolar disorder (BPD) exhibit alterations in their phospholipid levels. It is unclear whether these alterations are a secondary consequence of illness state, or if phospholipids and illness risk overlap genetically. If the latter were true, then phospholipids might provide key insights into the pathophysiology of the illness. Therefore, we rank-ordered phospholipid classes by their genetic overlap with BPD risk in order to establish which class might be most informative in terms of increasing our understanding of illness pathophysiology. Analyses were conducted in a sample of 558 individuals, unselected for BPD, from 38 extended pedigrees (average family size=14.79, range=2-82). We calculated a coefficient of relatedness for all family members of nine individuals with BPD in the sample (N=185); this coefficient was set to be zero in unrelated individuals (N=373). Then, under an endophenotype ranking value (ERV) approach, this scalar index was tested against 13 seru...

Nature communications, Jan 18, 2017

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial na... more The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for…