Genome wide association study of hippocampal subfield volume in PTSD cases and trauma-exposed controls

ABSTRACTBehavioral, structural, and functional neuroimaging have implicated the hippocampus as a critical brain region in PTSD pathogenesis. We conducted a GWAS of hippocampal subfield volumes in a sample of recent military veteran trauma survivors (n=157), including some with PTSD (n=66). Covariates in our analysis included lifetime PTSD diagnosis, sex, intracranial volume, genomic estimates of ancestry, and childhood trauma. Interactions between genetic variants and lifetime PTSD or childhood trauma were interrogated for SNPs with significant main effects. Several genetic associations surpassed correction for multiple testing for several hippocampal subfields, including fimbria, subiculum, cornu ammonis-1(CA1), and hippocampal amygdala transition area (HATA). One association replicated in an independent cohort of civilians with PTSD (rs12880795 in TUNAR with L-HATA volume, p=3.43 × 10-7 in the discovery and p=0.0004 in the replication cohort). However, the most significant association in the discovery data set was between rs6906714 in LINC02571 and R-fimbria volume (p=5.99 ×10-8, q=0.0056). Interestingly, the effect of rs6906714 on R-fimbria volume increased with childhood trauma (G*E interaction p=0.022). In addition to variants in long intergenic non-coding RNAs (lincRNAs), we identified SNPs associated with hippocampal subfield volume, which are also quantitative trait loci (QTLs) for genes involved in RNA editing of glutamate receptor subunits (GluRs), oxidative stress, and autoimmune disorders. Genomic regions, some with putative regulatory roles, influence the volume of hippocampal subfields. Neuroimaging phenotypes may offer important insight into the genetic architecture and neurobiological pathways relevant to PTSD, as well as in the identification of potential biomarkers and drug targets for PTSD.

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The Different Effect of Childhood Trauma on Amygdala and Hippocampus in Patients with Bipolar Disorder and Healthy Controls

European Psychiatry ◽

10.1016/j.eurpsy.2017.01.288 ◽

2017 ◽

Vol 41 (S1) ◽

pp. S92-S92 ◽

Cited By ~ 1

Author(s):

D. Janiri ◽

P. De Rossi ◽

A. Simonetti ◽

G. Spalletta ◽

G. Sani

Keyword(s):

Bipolar Disorder ◽

Childhood Trauma ◽

Negative Reinforcement ◽

Biological Response ◽

Childhood Trauma Questionnaire ◽

Hippocampal Subfields ◽

Cornu Ammonis ◽

Response To Stress ◽

Competing Interest ◽

The Impact

IntroductionChildhood trauma (CT) is a relevant environmental stressor for bipolar disorder (BP). Amygdala and hippocampus are key areas involved both in the pathophysiology of BP and in mediating the biological response to stress.ObjectivesStructural neuroimaging studies help clarifying neural correlates of the relationship between BP diagnosis and CT.AimsTo verify the impact of CT on amygdala and hippocampus and hippocampal subfields volumes in BP patients and healthy control (HC).MethodsWe assessed 105 outpatients, diagnosed with BPI or BPII according to DSM-IV-TR criteria, and 113 HC subjects. History of CT was obtained using the childhood trauma questionnaire (CTQ). High-resolution magnetic resonance imaging was performed on all subjects and volumes of amygdala, hippocampus, nucleus accumbens, caudate, pallidum, putamen, thalamus and hippocampal subfields were measured through FreeSurfer.ResultsAll deep gray matter structures were smaller in BP than HC. CT modulated the impact of the diagnosis on bilateral amygdala and hippocampus, in particular on subiculum, presubiculum and cornu ammonis CA1. It was associated with bilateral decreased volumes in HC and increased volumes in patients with BP.ConclusionsChildhood trauma impacts on the amygdala and hippocampus, brain areas involved in response to stress and emotion processing, and specifically on the hippocampal subfields most implicated in learning trough positive/negative reinforcement.Disclosure of interestThe authors have not supplied their declaration of competing interest.

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Genetic Associations with Bortezomib Mediated Neuropathy in Multiple Myeloma.

Blood ◽

10.1182/blood.v114.22.1794.1794 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1794-1794 ◽

Cited By ~ 1

Author(s):

Sophie L Corthals ◽

David C Johnson ◽

Yvonne de Knegt ◽

Hartmut Goldschmidt ◽

Henk Lokhorst ◽

...

Keyword(s):

Multiple Myeloma ◽

Research Funding ◽

Multiple Testing ◽

Biological Effects ◽

Critical Role ◽

Significant Snps ◽

Trend Test ◽

Genetic Associations ◽

Two Phase ◽

Data Set

Abstract Abstract 1794 Poster Board I-820 The proteasome inhibitor bortezomib has demonstrated high antitumor activity in multiple myeloma (MM). Peripheral neuropathy (PNP) is a dose-limiting toxicity of bortezomib, which typically occurs within the first cycles of bortezomib in 30-40% of MM patients. Although bortezomib induced PNP is manageable and reversible in most MM patients, no effective prophylactic treatment against PNP is available and bortezomib discontinuation is frequently required. Identifying patients at risk of neuropathy and understanding its pathogenesis is therefore of great importance. The mechanism underlying bortezomib induced PNP is unknown. To investigate whether genetic variation is associated with bortezomib induced PNP, a custom-built molecular inversion probe (MIP) based single nucleotide polymorphism (SNP) chip, designed by “Bank on a Cure” (BOAC)) was used, containing 3404 SNPs selected in “functional regions” within 983 genes representing cellular functions and pathways that may influence disease response, toxicities, complications, and survival. To explore SNP associations with bortezomib induced PNP we compared cases and controls in two phase 3 clinical trials. In the Dutch-German HOVON-65/GMMG-HD4 trial 3 cycles of Bortezomib/Doxorubicin/Dexamethason were given for induction, and 52 PNP grade 2,3,4 cases (37 %) were identified during this treatment against 84 controls. In the French IFM 2005-01 trial 4 cycles of Bortezomib/Dexamethasone were given, and 74 PNP grade 2,3,4 cases (34 %) versus 144 controls were identified. A Cochran-Armitage trend test was applied on the combined data set using the program PLINK. To account for multiple testing we carried out label swapping procedures. A set of SNPs was identified that was highly associated with bortezomib induced PNP. The 5 most significant SNPs are rs3136516 in F2 (thrombin) (p=2.0×10-4; Odds Ratio (OR)=0.53, 95% confidence interval (CI)=0.38-0.72), rs2686184 in FDFT1 (p=2.1×10-4; OR=1.6, 1.17-2.19), rs2137975 in DPYD (p=2.3×10-4; OR=1.60, 1.17-2.20), rs2857605 in TNF (p=3.0×10-3; OR=0.53, 0.35-0.79), rs12198787 in TNF (p=4.9×10-3; OR=0.48, 0.30-0.79). In addition, 3 significant SNPs (rs10979601, rs10759326 and rs838827) were located in IKBKAP, a gene involved in hereditary sensory neuropathies. Another interesting associated SNP, rs7096206 (p=8.5×10-3; OR=1.60, 1.10-2.32), is known to lead to reduced MBL2 serum levels. Significant associations were also seen in ADME genes (drug absorption, distribution, metabolism, and excretion) such as ABCC1, CYP2C9, CYP1A1, CYP1A2, CYP11B1, CYP17A1, CYP3A4, ABCB11, FMO2 and SLC22A4. Overall, the set of associated SNPs were enriched for genes in pathways involved in DNA replication, DNA repair, cell-to-cell signaling and drug metabolism. In conclusion, we identified a set of SNPs which are highly associated with bortezomib mediated PNP. Both ADME and critical biological pathways are implicated, which suggests a critical role for bortezomib metabolism and biological effects in PNP development. Our results open the way to develop a classifier predicting PNP in MM patients. Disclosures Off Label Use: Use of Bortezomib in first line treatment of Multiple Myeloma. Goldschmidt:Johnson and Johnson: Research Funding, Speakers Bureau. Lokhorst:Celgene: Consultancy. Sonneveld:Johnson and Johnson: Research Funding, Speakers Bureau.

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Genetic variation at the glycosaminoglycan metabolism pathway contributes to the risk of psoriatic arthritis but not psoriasis

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2018-214158 ◽

2018 ◽

Vol 78 (3) ◽

pp. 355-364 ◽

Cited By ~ 10

Author(s):

Adrià Aterido ◽

Juan D Cañete ◽

Jesús Tornero ◽

Carlos Ferrándiz ◽

José Antonio Pinto ◽

...

Keyword(s):

Genetic Variation ◽

Psoriatic Arthritis ◽

Drug Targets ◽

Genome Wide Association Study ◽

New Drugs ◽

Genetic Associations ◽

Metabolism Pathway ◽

A Genome ◽

Disease Specific ◽

Pathway Level

ObjectivePsoriatic arthritis (PsA) is a chronic inflammatory arthritis affecting up to 30% of patients with psoriasis (Ps). To date, most of the known risk loci for PsA are shared with Ps, and identifying disease-specific variation has proven very challenging. The objective of the present study was to identify genetic variation specific for PsA.MethodsWe performed a genome-wide association study in a cohort of 835 patients with PsA and 1558 controls from Spain. Genetic association was tested at the single marker level and at the pathway level. Meta-analysis was performed with a case–control cohort of 2847 individuals from North America. To confirm the specificity of the genetic associations with PsA, we tested the associated variation using a purely cutaneous psoriasis cohort (PsC, n=614) and a rheumatoid arthritis cohort (RA, n=1191). Using network and drug-repurposing analyses, we further investigated the potential of the PsA-specific associations to guide the development of new drugs in PsA.ResultsWe identified a new PsA risk single-nucleotide polymorphism at B3GNT2 locus (p=1.10e-08). At the pathway level, we found 14 genetic pathways significantly associated with PsA (pFDR<0.05). From these, the glycosaminoglycan (GAG) metabolism pathway was confirmed to be disease-specific after comparing the PsA cohort with the cohorts of patients with PsC and RA. Finally, we identified candidate drug targets in the GAG metabolism pathway as well as new PsA indications for approved drugs.ConclusionThese findings provide insights into the biological mechanisms that are specific for PsA and could contribute to develop more effective therapies.

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Childhood trauma moderates morphometric associations between orbitofrontal cortex and amygdala: implications for pathological personality traits

Psychological Medicine ◽

10.1017/s0033291720004468 ◽

2020 ◽

pp. 1-10

Author(s):

Nadia Bounoua ◽

Rickie Miglin ◽

Jeffrey M. Spielberg ◽

Curtis L. Johnson ◽

Naomi Sadeh

Keyword(s):

Personality Traits ◽

Childhood Trauma ◽

Orbitofrontal Cortex ◽

Functional Neuroimaging ◽

Trauma Exposure ◽

Diagnostic Interview ◽

Emotional Dysregulation ◽

Self Report ◽

Traumatic Experiences ◽

Pathological Personality Traits

Abstract Background Research has demonstrated that chronic stress exposure early in development can lead to detrimental alterations in the orbitofrontal cortex (OFC)–amygdala circuit. However, the majority of this research uses functional neuroimaging methods, and thus the extent to which childhood trauma corresponds to morphometric alterations in this limbic-cortical network has not yet been investigated. This study had two primary objectives: (i) to test whether anatomical associations between OFC–amygdala differed between adults as a function of exposure to chronic childhood assaultive trauma and (ii) to test how these environment-by-neurobiological effects relate to pathological personality traits. Methods Participants were 137 ethnically diverse adults (48.1% female) recruited from the community who completed a clinical diagnostic interview, a self-report measure of pathological personality traits, and anatomical MRI scans. Results Findings revealed that childhood trauma moderated bilateral OFC–amygdala volumetric associations. Specifically, adults with childhood trauma exposure showed a positive association between medial OFC volume and amygdalar volume, whereas adults with no childhood exposure showed the negative OFC–amygdala structural association observed in prior research with healthy samples. Examination of the translational relevance of trauma-related alterations in OFC–amygdala volumetric associations for disordered personality traits revealed that trauma exposure moderated the association of OFC volume with antagonistic and disinhibited phenotypes, traits characteristic of Cluster B personality disorders. Conclusions The OFC–amygdala circuit is a potential anatomical pathway through which early traumatic experiences perpetuate emotional dysregulation into adulthood and confer risk for personality pathology. Results provide novel evidence of divergent neuroanatomical pathways to similar personality phenotypes depending on early trauma exposure.

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Eyes of Africa: The Genetics of Blindness: Study Design and Methodology

BMC Ophthalmology ◽

10.1186/s12886-021-02029-8 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Olusola Olawoye ◽

Chimdi Chuka-Okosa ◽

Onoja Akpa ◽

Tony Realini ◽

Michael Hauser ◽

...

Keyword(s):

Genome Wide Association Study ◽

Case Control Study ◽

African Ancestry ◽

Collaborative Study ◽

Data Set ◽

Human Heredity ◽

Genome Wide ◽

A Genome ◽

Multiplex Families ◽

Control Study

Abstract Background This report describes the design and methodology of the “Eyes of Africa: The Genetics of Blindness,” a collaborative study funded through the Human Heredity and Health in Africa (H3Africa) program of the National Institute of Health. Methods This is a case control study that is collecting a large well phenotyped data set among glaucoma patients and controls for a genome wide association study. (GWAS). Multiplex families segregating Mendelian forms of early-onset glaucoma will also be collected for exome sequencing. Discussion A total of 4500 cases/controls have been recruited into the study at the end of the 3rd funded year of the study. All these participants have been appropriately phenotyped and blood samples have been received from these participants. Recent GWAS of POAG in African individuals demonstrated genome-wide significant association with the APBB2 locus which is an association that is unique to individuals of African ancestry. This study will add to the existing knowledge and understanding of POAG in the African population.

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A powerful and efficient two-stage method for detecting gene-to-gene interactions in GWAS

Biostatistics ◽

10.1093/biostatistics/kxw060 ◽

2017 ◽

Vol 18 (3) ◽

pp. 477-494 ◽

Cited By ~ 5

Author(s):

Jakub Pecanka ◽

Marianne A. Jonker ◽

Zoltan Bochdanovits ◽

Aad W. Van Der Vaart ◽

Keyword(s):

Complex Traits ◽

Multiple Testing ◽

Statistical Power ◽

Genome Wide Association Study ◽

Score Test ◽

Interaction Model ◽

Type I ◽

Two Stage ◽

Genome Wide ◽

Strong Control

Summary For over a decade functional gene-to-gene interaction (epistasis) has been suspected to be a determinant in the “missing heritability” of complex traits. However, searching for epistasis on the genome-wide scale has been challenging due to the prohibitively large number of tests which result in a serious loss of statistical power as well as computational challenges. In this article, we propose a two-stage method applicable to existing case-control data sets, which aims to lessen both of these problems by pre-assessing whether a candidate pair of genetic loci is involved in epistasis before it is actually tested for interaction with respect to a complex phenotype. The pre-assessment is based on a two-locus genotype independence test performed in the sample of cases. Only the pairs of loci that exhibit non-equilibrium frequencies are analyzed via a logistic regression score test, thereby reducing the multiple testing burden. Since only the computationally simple independence tests are performed for all pairs of loci while the more demanding score tests are restricted to the most promising pairs, genome-wide association study (GWAS) for epistasis becomes feasible. By design our method provides strong control of the type I error. Its favourable power properties especially under the practically relevant misspecification of the interaction model are illustrated. Ready-to-use software is available. Using the method we analyzed Parkinson’s disease in four cohorts and identified possible interactions within several SNP pairs in multiple cohorts.

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A Proteome-Wide Association Study Identified Candidate Human Brain Proteins Associated with Coffee Consumption

10.21203/rs.3.rs-910538/v1 ◽

2021 ◽

Author(s):

Chun'e Li ◽

Xiao Liang ◽

Yumeng Jia ◽

Yan Wen ◽

Huijie Zhang ◽

...

Keyword(s):

Human Brain ◽

Association Study ◽

Plasma Proteins ◽

Genome Wide Association Study ◽

Genetic Correlations ◽

Coffee Consumption ◽

Genetic Associations ◽

Brain Proteins ◽

Genome Wide ◽

Brain Proteome

Abstract Background Increasing evidence suggests the association between caffeine and the brain and nervous system. However, there is limited research on the genetic associations between coffee consumption subtypes and brain proteome, plasma proteomes, and peripheral metabolites. Methods First, proteome-wide association study (PWAS) of coffee consumption subtypes was performed by integrating two independent genome-wide association study (GWAS) datasets (91,462–502,650 subjects) with two reference human brain proteomes (ROS/MAP and Banner), by using the FUSION pipeline. Second, transcriptome-wide association study (TWAS) analysis of coffee consumption subtypes was conducted by integrating the two gene expression weight references (RNAseq and splicing) of brain RNA-seq and the two GWAS datasets (91,462–502,650 subjects) of coffee consumption subtypes. Finally, we used the LD Score Regression (LDSC) analysis to evaluate the genetic correlations of coffee consumption subtypes with plasma proteomes and peripheral metabolites. Results For the traits related to coffee consumption, we identified 3 common PWAS proteins, such as MADD (P PWAS−Banner−dis=0.0114, P PWAS−ROS/MAP−rep =0.0489). In addition, 11 common TWAS genes were found in two cohorts, such as ARPC2 (P TWAS−splicing−dis =2063×10− 12, P TWAS−splicing−dis =1.25×10− 10, P TWAS−splicing−dis =1.24e-08, P TWAS−splicing−rep =3.25×10− 9 and P TWAS−splicing−rep =3.42×10− 13). Importantly, we have identified 8 common genes between PWAS and TWAS, such as ALDH2 (P PWAS−banner−rep =1.22×10− 22, PTWAS− splicing−dis = 4.54×10− 92). For the LDSC analysis of human plasma proteome, we identified 11 plasma proteins, such as CHL1 (P dis = 0.0151, P rep =0.0438). For the LDSC analysis of blood metabolites, 5 metabolites have been found, such as myo-inositol (P dis = 0.0073, P dis = 0.0152, P dis =0.0414, P rep =0.0216). Conclusions We identified several brain proteins and genes associated with coffee consumption subtypes. In addition, we also detected several candidate plasma proteins and metabolites related to these subtypes.

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Testing for Trends in Dose-Response Microarray Experiments: A Comparison of Several Testing Procedures, Multiplicity and Resampling-Based Inference

Statistical Applications in Genetics and Molecular Biology ◽

10.2202/1544-6115.1283 ◽

2007 ◽

Vol 6 (1) ◽

Cited By ~ 14

Author(s):

Dan Lin ◽

Ziv Shkedy ◽

Dani Yekutieli ◽

Tomasz Burzykowski ◽

Hinrich W.H. Göhlmann ◽

...

Keyword(s):

Gene Expression ◽

Dose Response ◽

Multiple Testing ◽

Pharmaceutical Research ◽

Ratio Test ◽

Familywise Error Rate ◽

Response Level ◽

Data Set ◽

Monotonic Trend ◽

Testing Procedures

Dose-response studies are commonly used in experiments in pharmaceutical research in order to investigate the dependence of the response on dose, i.e., a trend of the response level toxicity with respect to dose. In this paper we focus on dose-response experiments within a microarray setting in which several microarrays are available for a sequence of increasing dose levels. A gene is called differentially expressed if there is a monotonic trend (with respect to dose) in the gene expression. We review several testing procedures which can be used in order to test equality among the gene expression means against ordered alternatives with respect to dose, namely Williams' (Williams 1971 and 1972), Marcus' (Marcus 1976), global likelihood ratio test (Bartholomew 1961, Barlow et al. 1972, and Robertson et al. 1988), and M (Hu et al. 2005) statistics. Additionally we introduce a modification to the standard error of the M statistic. We compare the performance of these five test statistics. Moreover, we discuss the issue of one-sided versus two-sided testing procedures. False Discovery Rate (Benjamni and Hochberg 1995, Ge et al. 2003), and resampling-based Familywise Error Rate (Westfall and Young 1993) are used to handle the multiple testing issue. The methods above are applied to a data set with 4 doses (3 arrays per dose) and 16,998 genes. Results on the number of significant genes from each statistic are discussed. A simulation study is conducted to investigate the power of each statistic. A R library IsoGene implementing the methods is available from the first author.

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Kleine-Levin syndrome is associated with birth difficulties and genetic variants in the TRANK1 gene loci

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2005753118 ◽

2021 ◽

Vol 118 (12) ◽

pp. e2005753118

Author(s):

Aditya Ambati ◽

Ryan Hillary ◽

Smaranda Leu-Semenescu ◽

Hanna M. Ollila ◽

Ling Lin ◽

...

Keyword(s):

Bipolar Disorder ◽

Genome Wide Association Study ◽

Perinatal Outcomes ◽

Case Control ◽

Risk Scores ◽

Circadian Regulation ◽

Genetic Associations ◽

Imaging Studies ◽

Genome Wide

Kleine-Levin syndrome (KLS) is a rare disorder characterized by severe episodic hypersomnia, with cognitive impairment accompanied by apathy or disinhibition. Pathophysiology is unknown, although imaging studies indicate decreased activity in hypothalamic/thalamic areas during episodes. Familial occurrence is increased, and risk is associated with reports of a difficult birth. We conducted a worldwide case−control genome-wide association study in 673 KLS cases collected over 14 y, and ethnically matched 15,341 control individuals. We found a strong genome-wide significant association (rs71947865, Odds Ratio [OR] = 1.48, P = 8.6 × 10−9) within the 3′region of TRANK1 gene locus, previously associated with bipolar disorder and schizophrenia. Strikingly, KLS cases with rs71947865 variant had significantly increased reports of a difficult birth. As perinatal outcomes have dramatically improved over the last 40 y, we further stratified our sample by birth years and found that recent cases had a significantly reduced rs71947865 association. While the rs71947865 association did not replicate in the entire follow-up sample of 171 KLS cases, rs71947865 was significantly associated with KLS in the subset follow-up sample of 59 KLS cases who reported birth difficulties (OR = 1.54, P = 0.01). Genetic liability of KLS as explained by polygenic risk scores was increased (pseudo R2 = 0.15; P < 2.0 × 10−22 at P = 0.5 threshold) in the follow-up sample. Pathway analysis of genetic associations identified enrichment of circadian regulation pathway genes in KLS cases. Our results suggest links between KLS, circadian regulation, and bipolar disorder, and indicate that the TRANK1 polymorphisms in conjunction with reported birth difficulties may predispose to KLS.

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Genetic Determinants of Telomere Length in African American Youth

10.1101/310417 ◽

2018 ◽

Author(s):

Andrew M. Zeiger ◽

Marquitta J. White ◽

Sam S. Oh ◽

Jonathan Witonsky ◽

Maria G. Contreras ◽

...

Keyword(s):

African American ◽

Telomere Length ◽

Genome Wide Association Study ◽

African Ancestry ◽

African American Youth ◽

Genetic Associations ◽

Disease States ◽

Genome Wide ◽

Pediatric Populations ◽

Genetic And Environmental Factors

ABSTRACTTelomere length (TL) is associated with numerous disease states and is affected by genetic and environmental factors. However, TL has been mostly studied in adult populations of European or Asian ancestry. These studies have identified 34 TL-associated genetic variants recently used as genetic proxies for TL. The generalizability of these associations to pediatric populations and racially diverse populations, specifically of African ancestry, remains unclear. Furthermore, six novel variants associated with TL in a population of European children have been identified but not validated. We measured TL from whole blood samples of 492 healthy African American youth (children and adolescents between 8 and 20 years old) and performed the first genome-wide association study of TL in this population. We were unable to replicate neither the 34 reported genetic associations found in adults nor the six genetic associations found in European children. However, we discovered a novel genome-wide significant association between TL and rs1483898 on chromosome 14. Our results underscore the importance of examining these genetic associations with TL in diverse pediatric populations such as African Americans.

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