scholarly journals Serotonin functioning and adolescents' alcohol use: A genetically informed study examining mechanisms of risk

2017 ◽  
Vol 30 (1) ◽  
pp. 213-233 ◽  
Author(s):  
Frances L. Wang ◽  
Laurie Chassin ◽  
John E. Bates ◽  
Danielle Dick ◽  
Jennifer E. Lansford ◽  
...  
Keyword(s):  
Depressive Symptoms ◽  
Alcohol Use ◽  
Parental Education ◽  
Genome Wide Association Study ◽  
Self Regulation ◽  
Risk Scores ◽  
Polygenic Risk ◽  
Genome Wide ◽  
Two Samples ◽  
Hydroxyindoleacetic Acid

AbstractThe current study used data from two longitudinal samples to test whether self-regulation, depressive symptoms, and aggression/antisociality were mediators in the relation between a polygenic score indexing serotonin (5-HT) functioning and alcohol use in adolescence. The results from an independent genome-wide association study of 5-hydroxyindoleacetic acid in the cerebrospinal fluid were used to create 5-HT polygenic risk scores. Adolescents and/or parents reported on adolescents’ self-regulation (Time 1), depressive symptoms (Time 2), aggression/antisociality (Time 2), and alcohol use (Time 3). The results showed that 5-HT polygenic risk did not predict self-regulation. However, adolescents with higher levels of 5-HT polygenic risk showed greater depression and aggression/antisociality. Adolescents’ aggression/antisociality mediated the relation between 5-HT polygenic risk and later alcohol use. Deficits in self-regulation also predicted depression and aggression/antisociality, and indirectly predicted alcohol use through aggression/antisociality. Pathways to alcohol use were especially salient for males from families with low parental education in one of the two samples. The results provide insights into the longitudinal mechanisms underlying the relation between 5-HT functioning and alcohol use (i.e., earlier aggression/antisociality). There was no evidence that genetically based variation in 5-HT functioning predisposed individuals to deficits in self-regulation. Genetically based variation in 5-HT functioning and self-regulation might be separate, transdiagnostic risk factors for several types of psychopathology.

scholarly journals Maternal Psychological Problems During Pregnancy and Child Externalizing Problems: Moderated Mediation Model with Child Self-regulated Compliance and Polygenic Risk Scores for Aggression

2021 ◽  
Author(s):  
Mannan Luo ◽  
Irene Pappa ◽  
Charlotte A. M. Cecil ◽  
Philip Jansen ◽  
Marinus H. van IJzendoorn ◽  
...  
Keyword(s):  
Externalizing Problems ◽  
Genome Wide Association Study ◽  
Self Regulation ◽  
Psychological Problems ◽  
Risk Scores ◽  
Mediation Model ◽  
Polygenic Risk ◽  
Moderated Mediation Model ◽  
Genome Wide ◽  
A Genome

AbstractA potential pathway underlying the association between prenatal exposure to maternal psychological problems and childhood externalizing problems is child self-regulation. This prospective study (N = 687) examined whether self-regulated compliance mediates the relation between maternal affective problems and hostility during pregnancy and childhood externalizing problems, and explored moderation by child polygenic risk scores for aggression and sex. Self-regulated compliance at age 3 was observed in mother–child interactions, and externalizing problems at age 6 were reported by mothers and teachers. Polygenic risk scores were calculated based on a genome-wide association study of aggressive behavior. Self-regulated compliance mediated the associations between maternal psychological problems and externalizing problems. Aggression PRS was associated with higher externalizing problems reported by mothers. No evidence was found of moderation by aggression PRS or sex. These findings support the hypothesis that maternal psychological problems during pregnancy might influence externalizing problems through early self-regulation, regardless of child genetic susceptibility or sex.

O-116 Genetic association analyses identify links between pelvic prolapse (PP) and connective tissue biology, cardiovascular and reproductive health

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
N Pujol Gualdo ◽  
K Läll ◽  
M Lepamets ◽  
R Arffman ◽  
T Piltonen ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Risk Scores ◽  
Polygenic Risk ◽  
Genome Wide ◽  
Meta Analyses ◽  
Personalized Risk

Abstract Study question Can genome-wide association analysis unravel the biological underpinnings of PP and facilitate personalized risk assessment via genetic risk scores construction? Summary answer We unravel novel links with urogenital development and vascular health in PP and present polygenic risk score as a tool to stratify PP risk. What is known already Prolapse is characterized by a descent of the pelvic organs into the vaginal cavity. PP affects around 40% of women after menopause and is the main indication for major gynecological surgery, having an important health, social and economic burden. Although the etiology and biological mechanisms underlying PP remain poorly understood, prior studies suggest genetic factors might play a role. Recently, a genome-wide association study (GWAS) identified seven genome-wide significant loci, located in or near genes involved in connective tissue metabolism and estrogen exposure in the etiology of PP. Study design, size, duration We conducted a three-stage case-control genome-wide association study. Firstly, in the discovery phase, we meta-analyzed Icelandic, UK Biobank and the FinnGen R3 datasets, comprising a total of 20118 cases and 427426 controls of European ancestry. For replication we used an independent dataset from Estonian Biobank (7968 cases and 118895 controls). Finally, we conducted a joint meta-analysis, containing 28086 cases and 546321 controls, which is the largest GWAS of PP to date. Participants/materials, setting, methods We performed functional annotation on genetic variants unraveled by GWAS and integrated these with expression quantitative trait loci and chromatin interaction data. In addition, we looked at enrichment of association signal on gene-set, tissue and cell type level and analyzed associations with other phenotypes both on genetic and phenotypic level. Colocalisation analyses were conducted to help pinpoint causal genes. We further constructed polygenic risk scores to explore options for personalized risk assessment and prevention. Main results and the role of chance In the discovery phase, we identified 18 genetic loci and 20 genetic variants significantly associated with POP (p < 5 × 10−8) and 75% of the variants show nominal significance association (p < 0.05) in the replication. Notably, the joint meta-analyses detected 20 genetic loci significantly associated with POP, from which 13 loci were novel. Novel genetic variants are located in or near genes involved in gestational duration and preterm birth (rs2687728 p = 2.19x10-9, EEFSEC), cardiovascular health and pregnancy success (rs1247943 p = 5.83x10-18, KLF13), endometriosis (rs12325192 p = 3.72x10-18, CRISPLD2), urogenital tract development (rs7126322, p = 4.35x10-15, WT1 and rs42400, p = 4.8x10-10, ADAMTS16) and regulation of the oxytocin receptor (rs2267372, p = 4.49x10-13, MAFF). Further analyses demonstrated that POP GWAS signals colocalise with several eQTLS (including EEFSEC, MAFF, KLF13, etc.), providing further evidence for mapping associated genes. Tissue and cell enrichment analyses underlined the role of the urogenital system, muscle cells, myocytes and adipocytes (p < 0.00001, FDR<0.05). Furthermore, genetic correlation analyses supported a shared genetic background with gastrointestinal disorders, joint and musculoskeletal disorders and cardiovascular disease. Polygenic risk scores analyses included a total of 125551 people in the target dataset, with 5379 prevalent patients and 2517 incident patients. Analyzing the best GRS as a quintile showed association with incident disease (Harrell c-statistic= 0.603, SD = 0.006). Limitations, reasons for caution This GWAS meta-analyses focused on European ancestry populations, which challenges the generalizability of GWAS findings to non-European populations. Moreover, this study included women with PP from population-based biobanks identified using the ICD-10 code N81, which limits analyses considering different disease stages and severity. Wider implications of the findings Our study provides genetic evidence to improve the current understanding of PP pathogenesis and serves as basis for further functional studies. Moreover, we provide a genetic tool for personalized risk stratification, which could help prevent PP development and improve the quality of a vast quantity of women. Trial registration number not applicable

scholarly journals The Power to Detect Cultural Transmission in the Nuclear Twin Family Design With and Without Polygenic Risk Scores and in the Transmitted–Nontransmitted (Alleles) Design

2020 ◽  
Vol 23 (5) ◽  
pp. 265-270
Author(s):  
Susanne Bruins ◽  
Conor V. Dolan ◽  
Dorret I. Boomsma
Keyword(s):  
Cultural Transmission ◽  
Genome Wide Association Study ◽  
Risk Scores ◽  
Data Simulation ◽  
Genetic Transmission ◽  
Polygenic Risk ◽  
Genome Wide ◽  
Appreciable Increase ◽  
Genome Wide Data ◽  
Recent Method

AbstractWe compare the power of two different approaches to detect passive genotype–environment (GE) covariance originating from cultural and genetic transmission operating simultaneously. In the traditional nuclear twin family (NTF) design, cultural transmission is estimated from the phenotypic covariance matrices of the mono- and dizygotic twins and their parents. Here, phenotyping is required in all family members. A more recent method is the transmitted–nontransmitted (T–NT) allele design, which exploits measured genetic variants in parents and offspring to test for effects of nontransmitted alleles from parents. This design requires two-generation genome-wide data and a powerful genome-wide association study (GWAS) for the phenotype in addition to phenotyping in offspring. We compared the power of both designs. Using exact data simulation, we demonstrate three points: how the power of the T–NT design depends on the predictive power of polygenic risk scores (PRSs); that when the NTF design can be applied, its power to detect cultural transmission and GE covariance is high relative to T–NT; and that, given effect sizes from contemporary GWAS, adding PRSs to the NTF design does not yield an appreciable increase in the power to detect cultural transmission. However, it may be difficult to collect phenotypes of parents and the possible importance of gene × age interaction, and secular generational effects can cause complications for many important phenotypes. The T–NT design avoids these complications.

scholarly journals Genome-wide association study of suicide attempt in psychiatric disorders identifies association with major depression polygenic risk scores

2018 ◽  
Author(s):  
Niamh Mullins ◽  
Tim B. Bigdeli ◽  
Anders D Børglum ◽  
Jonathan R I Coleman ◽  
Ditte Demontis ◽  
...  
Keyword(s):  
Major Depression ◽  
Suicide Attempt ◽  
Psychiatric Disorders ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Risk Scores ◽  
Genetic Associations ◽  
Suicide Attempters ◽  
Polygenic Risk ◽  
Genome Wide

AbstractObjectiveOver 90% of suicide attempters have a psychiatric diagnosis, however twin and family studies suggest that the genetic etiology of suicide attempt (SA) is partially distinct from that of the psychiatric disorders themselves. Here, we present the largest genome-wide association study (GWAS) on suicide attempt using major depressive disorder (MDD), bipolar disorder (BIP) and schizophrenia (SCZ) cohorts from the Psychiatric Genomics Consortium.MethodSamples comprise 1622 suicide attempters and 8786 non-attempters with MDD, 3264 attempters and 5500 non-attempters with BIP and 1683 attempters and 2946 non-attempters with SCZ. SA GWAS were performed comparing attempters to non-attempters in each disorder followed by meta-analysis across disorders. Polygenic risk scoring investigated the genetic relationship between SA and the psychiatric disorders.ResultsThree genome-wide significant loci for SA were found: one associated with SA in MDD, one in BIP, and one in the meta-analysis of SA in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. Polygenic risk scores for major depression were significantly associated with SA in MDD (P=0.0002), BIP (P=0.0006) and SCZ (P=0.0006).ConclusionsThis study provides new information on genetic associations and the genetic etiology of SA across psychiatric disorders. The finding that polygenic risk scores for major depression predict suicide attempt across disorders provides a possible starting point for predictive modelling and preventative strategies. Further collaborative efforts to increase sample size hold potential to robustly identify genetic associations and gain biological insights into the etiology of suicide attempt.

scholarly journals Genome-wide Association Study of Alcohol Consumption and Use Disorder in Multiple Populations (N = 274,424)

2019 ◽  
Author(s):  
Henry R. Kranzler ◽  
Hang Zhou ◽  
Rachel L. Kember ◽  
Rachel Vickers Smith ◽  
Amy C. Justice ◽  
...  
Keyword(s):  
Alcohol Consumption ◽  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
Genome Wide Association ◽  
Risk Scores ◽  
Genome Wide Association Studies ◽  
Cell Type ◽  
Polygenic Risk ◽  
Consumption Level ◽  
Genome Wide

SummaryAlthough alcohol consumption level and alcohol use disorder (AUD) diagnosis are both moderately heritable, their genetic risks and overlap are not well understood. We conducted genome-wide association studies of these traits using longitudinal Alcohol Use Disorder Identification Test-Consumption (AUDIT-C) scores (reflecting alcohol consumption) and AUD diagnoses from electronic health records (EHRs) in a single, large multi-ancestry Million Veteran Program sample. Meta-analysis across population groups (N = 274,424) identified 18 genome-wide significant loci, 5 of which were associated with both traits and 13 with either AUDIT-C (N = 8) or AUD (N = 5). A significant genetic correlation between the traits reflects this overlap. However, downstream analyses revealed biologically meaningful points of divergence. Cell-type group partitioning heritability enrichment analyses indicated that central nervous system was the most significant cell type for AUDIT-C and the only significant cell type for AUD. Polygenic risk scores (PRS) for both traits were associated with alcohol-related disorders in two independent samples. Genetic correlations for 188 non-alcohol-related traits were significantly different for the two traits, as were the phenotypes associated with the traits’ polygenic risk scores. We conclude that EHR-derived, longitudinal, repeated measures of alcohol consumption level and AUD diagnosis can facilitate genetic discovery and help to elucidate the relationship between drinking level and AUD risk. Finally, although heavy drinking is a key risk factor for AUD, it is not a sufficient cause of the disorder.

scholarly journals The power to detect cultural transmission in the Nuclear Twin Family design with and without polygenic risk scores and in the Transmitted-Non-transmitted (alleles) design

2020 ◽  
Author(s):  
S. Bruins ◽  
C. V. Dolan ◽  
D. I. Boomsma
Keyword(s):  
Cultural Transmission ◽  
Genome Wide Association Study ◽  
Risk Scores ◽  
Data Simulation ◽  
Genetic Transmission ◽  
Polygenic Risk ◽  
Genome Wide ◽  
Appreciable Increase ◽  
Genome Wide Data ◽  
Recent Method

AbstractThe aim of our study is to compare the power of two different approaches to detect passive genotype-environment covariance originating from simultaneous cultural and genetic transmission. In the traditional Nuclear Twin Family Design cultural transmission is estimated on the basis of the phenotypic covariance matrices of the mono- and dizygotic twins and their parents, where phenotyping is required in all family members. A more recent method is the Transmitted-Nontransmitted allele design, which exploits measured genetic variants in parents and offspring to test for effects of nontransmitted alleles from parents. This design requires genome-wide data and a powerful GWA (genome-wide association) study for the phenotype in addition to phenotyping in offspring. We compared the power of both designs. Using exact data simulation, we demonstrate that compared to the Transmitted-Nontransmitted design, the Nuclear Twin Family Design is relatively well-powered to detect cultural transmission and genotype-environment covariance. The power of the Transmitted-Nontransmitted design depends on the predictive power of polygenic risk scores. Adding polygenic risk scores of realistic effect size to the Nuclear Twin Family Design did not result in an appreciable increase the power to detect cultural transmission.

scholarly journals Polygenic prediction of lipid traits in sub-Saharan Africans

2021 ◽  
Author(s):  
Segun Fatumo ◽  
Abram Kamiza ◽  
Sounkou Toure ◽  
Marijana Vujkovic ◽  
Tafadzwa Machipisa ◽  
...  
Keyword(s):  
South African ◽  
Genome Wide Association Study ◽  
Risk Scores ◽  
Clinical Factors ◽  
Discriminatory Ability ◽  
Polygenic Risk ◽  
Genome Wide ◽  
Extreme Phenotypes ◽  
Sub Saharan ◽  
Conventional Risk Factors

Abstract Polygenic risk scores (PRS) can enhance risk stratification and are useful for precision medicine interventions. Here we show that African American Genome-wide Association Study (GWAS) derived PRS enhance prediction of lipid traits in Sub-Saharan Africans. Our PRS prediction varied greatly between South African Zulus (LDL-C, R2 = 8.49%) and Ugandans (LDL-C, R2= 0.043%), potentially attributable to environmental factors. Moreover, the PRS shown here had a higher discriminatory ability (AUC = 74.6%) than conventional risk factors (AUC= 67.8%) to identify extreme phenotypes. This work highlights the utility of PRS derived from relevant ethnic groups for identifying high-risk cases missed by conventional clinical factors.

scholarly journals O2.4. FUNCTIONAL CONNECTOME-WIDE ASSOCIATIONS OF SCHIZOPHRENIA POLYGENIC RISK

2020 ◽  
Vol 46 (Supplement_1) ◽  
pp. S4-S5
Author(s):  
Hengyi Cao ◽  
Hang Zhou ◽  
Tyrone Cannon
Keyword(s):  
Network Architecture ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Brain Connectivity ◽  
Bipolar Disorders ◽  
Principal Component ◽  
Risk Scores ◽  
Polygenic Risk ◽  
Genome Wide ◽  
Human Connectome Project

Abstract Background The relationships between schizophrenia polygenic risk and connectome-wide brain connectivity remain unclear. In particular, it is unknown whether and how schizophrenia polygenic risk would influence functional connectivity both at the connectome level and in a state-independent way. In this study, we used multi-paradigm fMRI data from two independent cohorts to investigate these questions. Methods The discovery sample included 623 healthy Caucasian participants (age 28.86 ± 3.63 years, 302 males) acquired from the Human Connectome Project (HCP). All subjects completed fMRI scans for a battery of eight paradigms and had imputed genetic data available. Following the procedures in our prior studies, we constructed whole-brain connectivity matrices for each paradigm in each individual. From these derived matrices, we computed cross-paradigm connectivity (CPC) using principal component analysis. These CPC matrices quantify shared connectivity patterns across all paradigms for each individual and thus represent state-independent “trait” network architecture of each subject. The polygenic risk scores (PRSs) for each subject were calculated based on the genome-wide association study (GWAS) results from the Psychiatric Genomics Consortium. The scores were calculated as the sum of genome-wide risk alleles for each individual, weighted by the corresponding odds ratios to schizophrenia. We report our main findings based on the GWAS-significant threshold (P = 5×10–8). In addition, to test the robustness of our findings, we also calculated PRSs with a set of other thresholds ranging from 5×10–7 to 5×10–2. The network-based statistic (NBS) analysis was performed to associate PRSs with CPC matrices, where age, sex, and head motion were included as covariates. Significance was determined by 10,000 permutations of the original sample. The validation sample included 44 patients with schizophrenia, 43 patients with bipolar disorders, 34 patients with attention deficit hyperactivity disorder, and 77 healthy controls drawn from the Consortium for Neuropsychiatric Phenomics (CNP). All subjects completed a battery of seven fMRI paradigms. We used this sample to examine 1) whether the identified connectomic findings were specifically detected in patients with schizophrenia; and 2) whether these findings could be related to behavioral deficits in patients with schizophrenia. Results In the HCP sample, the NBS analysis revealed a significant association (PFWE < 0.05) between schizophrenia PRS and a large-scale network involving a total of 69 edges connecting between 54 nodes. These nodes were predominantly distributed in the brain’s visual system, default-mode system, and frontoparietal system. Specifically, higher PRSs were associated with lower connectivity for all connections in the identified network (R = -0.37). The results were significant across all paradigms (R < -0.13, P < 0.001) and remained robust across multiple PRS thresholds (R < -0.10, P < 0.02). In the CNP sample, the connectivity of the detected network differed significantly between groups (P = 0.005), which was particularly driven by decreased connectivity in patients with SZ compared with that in HCs (PBonferroni = 0.03). The connectivity of the identified network was significantly correlated with both performance IQ (R = 0.28, P =0.002) and verbal IQ (R = 0.29, P = 0.001). Discussion These findings provide the first evidence for state-independent connectome-wide associations of schizophrenia polygenic risk at the systems level and suggest that disrupted integration of sensori-cognitive information may be a hallmark of genetic effects on the brain that contributes to the pathogenesis of schizophrenia.

Genome-wide investigation of alcohol response : a meta-analytic review and polygenic associations with alcohol use disorder

2020 ◽  
Author(s):  
◽  
Joseph D. Deak
Keyword(s):  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
Meta Analysis ◽  
Genotype Imputation ◽  
Genetic Influences ◽  
Risk Scores ◽  
Individual Study ◽  
Polygenic Risk ◽  
Gene Set ◽  
Genome Wide

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI-COLUMBIA AT REQUEST OF AUTHOR.] The current study aimed to extend previous genetic studies of level of response (LR) to alcohol by conducting the largest genome-wide association study (GWAS) of LR to date through the meta-analysis of multiple samples with extant SRE (Self-rating of the Effects of Alcohol) and GWAS data. A second aim was to use summary data from the described GWAS of LR to create polygenic risk scores (PRS) in an independent sample in order to determine whether, and to what extent, the genetic influences underlying LR to alcohol serve as a risk factor for alcohol use disorder (AUD). Towards these aims, datasets were processed according to standard quality control (QC) procedures allowing for genotype imputation and GWA analysis using methods appropriate for the individual study designs. Following individual study-level GWAS analysis, results were meta-analyzed utilizing an inverse-variance weighted fixed-effects model in METAL resulting in a final sample size of N=10,635. GWAS summary statistics from the SRE meta-analysis were then used to conduct gene-based and gene-set analyses, as well as compute polygenic risk scores (PRS) in an independent target sample to examine the predictive ability of the LR to alcohol PRS for DSM-IV AD symptom counts. No individual variants, genes, or gene-sets achieved study-level significance, although multiple genetic loci of interest achieved suggestive significance. The top single variant association was in an intergenic region on chromosome 2 located near the FUNDC2P2 gene (rs12463481; p=6.35x10[superscript -8]), the top gene-based association was with the PRR16 gene on chromosome 5 (p=6.72x10 [superscript -6]), and the top gene-set was with a set of genes associated with NFE2L2 targets (p=1.21 x10 [superscript -5]). No results from the PRS analysis approached significance. These findings suggest that, similar to other alcohol use outcomes, larger sample sizes will be required for the robust detection of genetic influences contributing to level of response to alcohol.

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