T173. POLYGENETIC RISK SCORES FOR MAJOR PSYCHIATRIC DISORDERS AMONG SCHIZOPHRENIA PATIENTS, THEIR FIRST-DEGREE RELATIVES AND HEALTHY SUBJECTS

Abstract Background The genetic etiology of schizophrenia (SCZ) overlaps with that of other major psychiatric disorders in samples of European ancestry. On the other hand, these major psychiatric disorders are distinct diagnoses that have disorder-specific genetic factors. Recently, the bipolar disorder (BIP) and SCZ Working Group of the PGC identified two genome-wide significant loci differentiating the two disorders in individuals of European descent. We hypothesized that genetic variants differentiating SCZ from BIP in Europeans as well as genetic variants related to psychiatric disorders in Europeans would overlap with genetic risk variants in Japanese SCZ patients and unaffected first-degree relatives (FRs), i.e., individuals at high risk of developing SCZ. The present study investigated transethnic polygenetic features shared between Japanese SCZ or their unaffected FRs and European patients with major psychiatric disorders by conducting polygenic risk score (PRS) analyses. Methods To calculate PRSs for five psychiatric disorders [SCZ, BIP, major depressive disorder (MDD), autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD)] and PRSs differentiating SCZ from BIP, we utilized large-scale European genome-wide association study (GWAS) datasets as discovery samples. PRSs derived from these GWASs were calculated for 335 Japanese target subjects [131 SCZ patients, 57 of their unaffected FRs and 147 healthy controls (HCs)]. We took these PRSs based on GWASs of European psychiatric disorders (SCZ, BIP, SCZ vs BIP, MDD, ASD and ADHD) and investigated their effect on risk in Japanese SCZ patients [(i) SCZ vs FRs vs HCs, (ii) SCZ vs HCs and (iii) SCZ vs FRs] or unaffected FRs [(iv) FRs vs HCs] by PRS analyses. Results The PRSs obtained from European SCZ samples were significantly higher in Japanese patients with SCZ than in HCs [(i) SCZ vs FRs vs HCs, a maximum at PT≤1.0: adjusted R2=0.028, p=1.30×10–3; (ii) SCZ vs HCs, a maximum at PT≤1.0: Nagelkerke’s R2=0.049, p=1.66×10–3]. In addition, the PRSs related to European BIP were nominally higher in Japanese patients with SCZ than in HCs [(i) SCZ vs FRs vs HCs, a maximum at PT≤0.5: adjusted R2=0.016, p=0.012; (ii) SCZ vs HCs, a maximum at PT≤0.5: Nagelkerke’s R2=0.029, p=0.015]. Furthermore, PRSs differentiating SCZ patients from European BIP patients were marginally higher in Japanese SCZ patients than in HCs [(i) SCZ vs FRs vs HCs, a maximum at PT≤0.05: adjusted R2=0.010, p=0.043; (ii) SCZ vs HCs, a maximum at PT≤0.05: Nagelkerke’s R2=0.020, p=0.046]. Interestingly, the PRSs obtained from European ASD were marginally lower in Japanese FRs compared with HCs [(iv) FRs vs HCs, a maximum at PT≤0.01: Nagelkerke’s R2=0.045, p=0.013] and patients with SCZ [(iii) SCZ vs FRs, a maximum at PT≤0.2: Nagelkerke’s R2=0.023, p=0.084]. As childhood-onset patients with SCZ have showed higher PRSs for both SCZ and ASD than their unaffected siblings, we further investigated the correlation between age at onset and PRSs for both SCZ and ASD in our SCZ samples. Lower age at onset of SCZ was significantly associated with higher PRSs for ASD (PT≤0.05: beta=-0.20, p=7.13×10–3) but not PRSs for SCZ (p>0.05). Discussion These findings suggest that polygenic factors related to European SCZ and BIP and the polygenic components differentiating SCZ from BIP can transethnically contribute to SCZ risk in Japanese people. Furthermore, we suggest that reduced levels of an ASD-related genetic factor in unaffected FRs may help protect against SCZ development.

Download Full-text

Polygenetic Risk Scores for Major Psychiatric Disorders Among Schizophrenia Patients, Their First-Degree Relatives, and Healthy Participants

The International Journal of Neuropsychopharmacology ◽

10.1093/ijnp/pyz073 ◽

2020 ◽

Vol 23 (3) ◽

pp. 157-164 ◽

Cited By ~ 2

Author(s):

Kazutaka Ohi ◽

Daisuke Nishizawa ◽

Takamitsu Shimada ◽

Yuzuru Kataoka ◽

Junko Hasegawa ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Psychiatric Disorders ◽

Large Scale ◽

Genome Wide Association Study ◽

Autism Spectrum ◽

Spectrum Disorder ◽

European Ancestry ◽

Risk Scores ◽

Polygenic Risk Score ◽

First Degree Relatives

Abstract Background The genetic etiology of schizophrenia (SCZ) overlaps with that of other major psychiatric disorders in samples of European ancestry. The present study investigated transethnic polygenetic features shared between Japanese SCZ or their unaffected first-degree relatives and European patients with major psychiatric disorders by conducting polygenic risk score (PRS) analyses. Methods To calculate PRSs for 5 psychiatric disorders (SCZ, bipolar disorder [BIP], major depressive disorder, autism spectrum disorder, and attention-deficit/hyperactivity disorder) and PRSs differentiating SCZ from BIP, we utilized large-scale European genome-wide association study (GWAS) datasets as discovery samples. PRSs derived from these GWASs were calculated for 335 Japanese target participants [SCZ patients, FRs, and healthy controls (HCs)]. We took these PRSs based on GWASs of European psychiatric disorders and investigated their effect on risk in Japanese SCZ patients and unaffected first-degree relatives. Results The PRSs obtained from European SCZ and BIP patients were higher in Japanese SCZ patients than in HCs. Furthermore, PRSs differentiating SCZ patients from European BIP patients were higher in Japanese SCZ patients than in HCs. Interestingly, PRSs related to European autism spectrum disorder were lower in Japanese first-degree relatives than in HCs or SCZ patients. The PRSs of autism spectrum disorder were positively correlated with a young onset age of SCZ. Conclusions These findings suggest that polygenic factors related to European SCZ and BIP and the polygenic components differentiating SCZ from BIP can transethnically contribute to SCZ risk in Japanese people. Furthermore, we suggest that reduced levels of an ASD-related genetic factor in unaffected first-degree relatives may help protect against SCZ development.

Download Full-text

Common genetic variants shared among five major psychiatric disorders: a large-scale genome-wide combined analysis

Global Clinical and Translational Research ◽

10.36316/gcatr.01.0003 ◽

2019 ◽

pp. 21-30 ◽

Cited By ~ 3

Author(s):

Lu Xia ◽

Kun Xia ◽

Daniel Weinberger ◽

Fengyu Zhang

Keyword(s):

Psychiatric Disorders ◽

Genetic Variants ◽

Autism Spectrum ◽

Epigenetic Mechanism ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Childhood Disorders ◽

Genome Wide ◽

Common Genetic Variants ◽

Genome Wide Significance

Background. Genetic correlation and pleiotropic effects among psychiatric disorders have been reported. This study aimed to identify specific common genetic variants shared between five adult psychiatric disorders: schizophrenia, bipolar, major depressive disorder, attention deficit-hyperactivity disorder, and autism spectrum disorder. Methods. A combined p-value of about 8 million single nucleotide polymorphisms (SNPs) was calculated in an equivalent sample of 151,672 cases and 284,444 controls of European ancestry from published data based on the latest genome-wide association studies of five major psychiatric disorder. SNPs that achieved genome-wide significance (P<5x10-08) were mapped to loci and genomic regions for further investigation; gene annotation and clustering were performed to understand the biological process and molecular function of the loci identified. We also examined CNVs and performed expression quantitative trait loci analysis for SNPs by genomic region. Results. We find that 6,293 SNPs mapped to 336 loci shared by the three adult psychiatric disorders, 1,108 variants at 73 loci shared by the childhood disorders, and 713 variants at 47 genes shared by all five disorders at genome-wide significance (P<5x10-08). Of the 2,583 SNPs at the extended major histocompatibility complex identified for three adult disorders, none of them were associated with childhood disorders; and SNPs shared by all five disorders were located in regions that have been identified as containing copy number variation associated with autism and had largely neurodevelopmental functions. Conclusion. We show a number of specific SNPs associated with psychiatric disorders of childhood or adult-onset, illustrating not only genetic heterogeneity across these disorders but also developmental genes shared by them all. These results provide a manageable list of anchors from which to investigate epigenetic mechanism or gene-gene interaction on the development of neuropsychiatric disorders and for developing a measurement matrix for disease risk to potentially develop a novel taxonomy for precision medicine.

Download Full-text

Performance of polygenic risk scores for cancer prediction in an academic biobank.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.1528 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 1528-1528

Author(s):

Heena Desai ◽

Anh Le ◽

Ryan Hausler ◽

Shefali Verma ◽

Anurag Verma ◽

...

Keyword(s):

Risk Score ◽

Genetic Variants ◽

Association Studies ◽

Risk Scores ◽

Polygenic Risk Score ◽

Genome Wide Association Studies ◽

Polygenic Risk ◽

European Americans ◽

Genome Wide ◽

Common Genetic Variants

1528 Background: The discovery of rare genetic variants associated with cancer have a tremendous impact on reducing cancer morbidity and mortality when identified; however, rare variants are found in less than 5% of cancer patients. Genome wide association studies (GWAS) have identified hundreds of common genetic variants significantly associated with a number of cancers, but the clinical utility of individual variants or a polygenic risk score (PRS) derived from multiple variants is still unclear. Methods: We tested the ability of polygenic risk score (PRS) models developed from genome-wide significant variants to differentiate cases versus controls in the Penn Medicine Biobank. Cases for 15 different cancers and cancer-free controls were identified using electronic health record billing codes for 11,524 European American and 5,994 African American individuals from the Penn Medicine Biobank. Results: The discriminatory ability of the 15 PRS models to distinguish their respective cancer cases versus controls ranged from 0.68-0.79 in European Americans and 0.74-0.93 in African Americans. Seven of the 15 cancer PRS trended towards an association with their cancer at a p<0.05 (Table), and PRS for prostate, thyroid and melanoma were significantly associated with their cancers at a bonferroni corrected p<0.003 with OR 1.3-1.6 in European Americans. Conclusions: Our data demonstrate that common variants with significant associations from GWAS studies can distinguish cancer cases versus controls for some cancers in an unselected biobank population. Given the small effects, future studies are needed to determine how best to incorporate PRS with other risk factors in the precision prediction of cancer risk. [Table: see text]

Download Full-text

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

Human Reproduction ◽

10.1093/humrep/deab126.025 ◽

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

Download Full-text

Common variants in Alzheimer’s disease: Novel association of six genetic variants with AD and risk stratification by polygenic risk scores

10.1101/19012021 ◽

2019 ◽

Cited By ~ 8

Author(s):

Itziar de Rojas ◽

Sonia Moreno-Grau ◽

Niccolò Tesi ◽

Benjamin Grenier-Boley ◽

Victor Andrade ◽

...

Keyword(s):

Genetic Variants ◽

Case Control Study ◽

Risk Group ◽

Age At Onset ◽

Case Control ◽

Risk Scores ◽

Polygenic Risk ◽

Genome Wide ◽

Similar Risk ◽

Control Study

ABSTRACTBACKGROUNDDisentangling the genetic constellation underlying Alzheimer’s disease (AD) is important. Doing so allows us to identify biological pathways underlying AD, point towards novel drug targets and use the variants for individualised risk predictions in disease modifying or prevention trials. In the present work we report on the largest genome-wide association study (GWAS) for AD risk to date and show the combined utility of proven AD loci for precision medicine using polygenic risk scores (PRS).METHODSThree sets of summary statistics were included in our meta-GWAS of AD: an Spanish case-control study (GR@ACE/DEGESCO study, n = 12,386), the case-control study of International Genomics of Alzheimer project (IGAP, n = 82,771) and the UK Biobank (UKB) AD-by-proxy case-control study (n=314,278). Using these resources, we performed a fixed-effects inverse-variance-weighted meta-analysis. Detected loci were confirmed in a replication study of 19,089 AD cases and 39,101 controls from 16 European-ancestry cohorts not previously used. We constructed a weighted PRS based on the 39 AD variants. PRS were generated by multiplying the genotype dosage of each risk allele for each variant by its respective weight, and then summing across all variants. We first validated it for AD in independent data (assessing effects of sub-threshold signal, diagnostic certainty, age at onset and sex) and tested its effect on risk (odds for disease) and age at onset in the GR@ACE/DEGESCO study.FINDINGSUsing our meta-GWAS approach and follow-up analysis, we identified novel genome-wide significant associations of six genetic variants with AD risk (rs72835061-CHRNE, rs2154481-APP, rs876461-PRKD3/NDUFAF7, rs3935877-PLCG2 and two missense variants: rs34173062/rs34674752 in SHARPIN gene) and confirmed a stop codon mutation in the IL34 gene increasing the risk of AD (IL34-Tyr213Ter), and two other variants in PLCG2 and HS3ST1 regions. This brings the total number of genetic variants associated with AD to 39 (excluding APOE). The PRS based on these variants was associated with AD in an independent clinical AD-case control dataset (OR=1.30, per 1-SD increase in the PRS, 95%CI 1.18-1.44, p = 1.1×10−7), a similar effect to that in the GR@ACE/DEGESCO (OR=1.27, 95%CI 1.23-1.32, p = 7.4×10−39). We then explored the combined effects of these 39 variants in a PRS for AD risk and age-at-onset stratification in GR@ACE/DEGESCO. Excluding APOE, we observed a gradual risk increase over the 2% tiles; when comparing the extremes, those with the 2% highest risk had a 2.98-fold (95% CI 2.12–4.18, p = 3.2×10−10) increased risk compared to those with the 2% lowest risk (p = 5.9×10−10). Using the PRS we identified APOE ε33 carriers with a similar risk as APOE ε4 heterozygotes carriers, as well as APOE ε4 heterozygote carriers with a similar risk as APOE ε4 homozygote. Considering age at onset; there was a 9-year difference between median onset of AD the lowest risk group and the highest risk group (82 vs 73 years; p = 1.6×10−6); a 4-year median onset difference (81 vs 77 years; p = 6.9×10−5) within APOE ε4 heterozygotes and a 5.5-year median onset difference (78.5 vs 73 years; p = 4.6×10−5) within APOE ε4 carriers.INTERPRETATIONWe identified six novel genetic variants associated with AD-risk, among which one common APP variant. A PRS of all genetic loci reported to date could be a robust tool to predict the risk and age at onset of AD, beyond APOE alone. These properties make PRS instrumental in selecting individuals at risk in order to apply preventative strategies and might have potential use in diagnostic work-up.

Download Full-text

Polygenic Risk Score of Sporadic late Onset Alzheimer Disease Reveals a Shared Architecture with the Familial and Early Onset Forms

10.1101/165209 ◽

2017 ◽

Cited By ~ 1

Author(s):

Jorge L Del-Aguila ◽

Benjamin Saef ◽

Kathleen Black ◽

Maria Victoria Fernandez ◽

John Budde ◽

...

Keyword(s):

Early Onset ◽

Genetic Architecture ◽

Late Onset ◽

Age At Onset ◽

Risk Scores ◽

Polygenic Risk Score ◽

Polygenic Risk ◽

Risk Variants ◽

Genome Wide ◽

Load Risk

AbstractObjective:To determine whether the genetic architecture of sporadic late-onset Alzheimer’s Disease (sLOAD) has an effect on familial late-onset AD (fLOAD), sporadic early-onset (sEOAD) and autosomal dominant early-onset (eADAD).Methods:Polygenic risk scores (PRS) were constructed using previously identified 21 genome-wide significant loci for LOAD risk.Results:We found that there is an overlap in the genetic architecture among sEOAD, fLOAD, and sLOAD. sEOAD showed the highest odds for the PRS (OR=2.27; p=1.29×10-7), followed by fLOAD (OR=1.75; p=1.12×10-7) and sLOAD (OR=1.40; p=1.21×10-3). PRS is associated with cerebrospinal fluid ptau181-Aβ42on eADAD.Conclusion:Our analysis confirms that the genetic factors identified for sLOAD also modulate risk in fLOAD and sEOAD cohorts. Furthermore, our results suggest that the burden of these risk variants is associated with familial clustering and earlier-onset of AD. Although these variants are not associated with risk in the eADAD, they may be modulating age at onset.

Download Full-text

Risk and coaggregation of major psychiatric disorders among first-degree relatives of patients with bipolar disorder: a nationwide population-based study

Psychological Medicine ◽

10.1017/s003329171800332x ◽

2018 ◽

Vol 49 (14) ◽

pp. 2397-2404 ◽

Cited By ~ 7

Author(s):

Mu-Hong Chen ◽

Ju-Wei Hsu ◽

Kei-Lin Huang ◽

Tung-Ping Su ◽

Cheng-Ta Li ◽

...

Keyword(s):

Bipolar Disorder ◽

Psychiatric Disorders ◽

Population Based ◽

Autism Spectrum ◽

The Public ◽

First Degree Relatives ◽

Relative Risks ◽

Dependent Relationship ◽

Increased Risk ◽

Bipolar Patients

AbstractBackgroundBipolar disorder is a highly heritable mental illness that transmits intergeneratively. Previous studies supported that first-degree relatives (FDRs), such as parents, offspring, and siblings, of patients with bipolar disorder, had a higher risk of bipolar disorder. However, whether FDRs of bipolar patients have an increased risk of schizophrenia, major depressive disorder (MDD), autism spectrum disorder (ASD), and attention deficit hyperactivity disorder (ADHD) remains unclear.MethodsAmong the entire population in Taiwan, 87 639 patients with bipolar disorder and 188 290 FDRs of patients with bipolar disorder were identified in our study. The relative risks (RRs) of major psychiatric disorders were assessed among FDRs of patients with bipolar disorder.ResultsFDRs of patients with bipolar disorder were more likely to have a higher risk of major psychiatric disorders, including bipolar disorder (RR 6.12, 95% confidence interval (CI) 5.95–6.30), MDD (RR 2.89, 95% CI 2.82–2.96), schizophrenia (RR 2.64, 95% CI 2.55–2.73), ADHD (RR 2.21, 95% CI 2.13–2.30), and ASD (RR 2.10, 95% CI 1.92–2.29), than the total population did. These increased risks for major psychiatric disorders were consistent across different familial kinships, such as parents, offspring, siblings, and twins. A dose-dependent relationship was also found between risk of each major psychiatric disorder and numbers of bipolar patients.ConclusionsOur study was the first study to support the familial coaggregation of bipolar disorder with other major psychiatric disorders, including schizophrenia, MDD, ADHD, and ASD, in a Taiwanese (non-Caucasian) population. Given the elevated risks of major psychiatric disorders, the public health government should pay more attention to the mental health of FDRs of patients with bipolar disorder.

Download Full-text

Increasing Sample Diversity in Psychiatric Genetics – Introducing a new Cohort of Patients with Schizophrenia and Controls from Vietnam – Results from a Pilot Study

10.1101/2021.04.21.21255615 ◽

2021 ◽

Author(s):

VT Nguyen ◽

A Braun ◽

J Kraft ◽

TMT Ta ◽

GM Panagiotaropoulou ◽

...

Keyword(s):

Pilot Study ◽

Data Collection ◽

Predictive Power ◽

Association Studies ◽

East Asian ◽

Genetic Research ◽

European Ancestry ◽

Risk Scores ◽

Genome Wide Association Studies ◽

Genome Wide

AbstractObjectivesGenome-Wide Association Studies (GWAS) of Schizophrenia (SCZ) have provided new biological insights; however, most cohorts are of European ancestry. As a result, derived polygenic risk scores (PRS) show decreased predictive power when applied to populations of different ancestries. We aimed to assess the feasibility of a large-scale data collection in Hanoi, Vietnam, contribute to international efforts to diversify ancestry in SCZ genetic research and examine the transferability of SCZ-PRS to individuals of Vietnamese Kinh ancestry.MethodsIn a pilot study, 368 individuals (including 190 SCZ cases) were recruited at the Hanoi Medical University’s associated psychiatric hospitals and outpatient facilities. Data collection included sociodemographic data, baseline clinical data, clinical interviews assessing symptom severity and genome-wide SNP genotyping. SCZ-PRS were generated using different training data sets: i) European, ii) East-Asian and iii) trans-ancestry GWAS summary statistics from the latest SCZ GWAS meta-analysis.ResultsSCZ-PRS significantly predicted case status in Vietnamese individuals using mixed-ancestry (R2 liability=4.9%, p=6.83*10−8), East-Asian (R2 liability=4.5%, p=2.73*10−7) and European (R2 liability=3.8%, p = 1.79*10−6) discovery samples.DiscussionOur results corroborate previous findings of reduced PRS predictive power across populations, highlighting the importance of ancestral diversity in GWA studies.

Download Full-text

Abstract PO-163: Genome-wide polygenic risk score of prostate cancer in African and European ancestry men

10.1158/1538-7755.disp21-po-163 ◽

2022 ◽

Author(s):

Burcu F. Darst ◽

Ravi K Madduri ◽

Alexis A. Rodriguez ◽

Xin Sheng ◽

Rosalind A. Eeles ◽

...

Keyword(s):

Prostate Cancer ◽

Risk Score ◽

European Ancestry ◽

Polygenic Risk Score ◽

Polygenic Risk ◽

Genome Wide

Download Full-text

Assessing the Causal Effects of Human Serum Metabolites on 5 Major Psychiatric Disorders

Schizophrenia Bulletin ◽

10.1093/schbul/sbz138 ◽

2020 ◽

Vol 46 (4) ◽

pp. 804-813 ◽

Cited By ~ 2

Author(s):

Jian Yang ◽

Bin Yan ◽

Binbin Zhao ◽

Yajuan Fan ◽

Xiaoyan He ◽

...

Keyword(s):

Human Serum ◽

Psychiatric Disorders ◽

Genetic Variants ◽

Association Studies ◽

Autism Spectrum ◽

Causal Effects ◽

Human Diseases ◽

Genome Wide Association Studies ◽

Serum Metabolites ◽

Intermediate Phenotypes

Abstract Psychiatric disorders are the leading cause of disability worldwide while the pathogenesis remains unclear. Genome-wide association studies (GWASs) have made great achievements in detecting disease-related genetic variants. However, functional information on the underlying biological processes is often lacking. Current reports propose the use of metabolic traits as functional intermediate phenotypes (the so-called genetically determined metabotypes or GDMs) to reveal the biological mechanisms of genetics in human diseases. Here we conducted a two-sample Mendelian randomization analysis that uses GDMs to assess the causal effects of 486 human serum metabolites on 5 major psychiatric disorders, which respectively were schizophrenia (SCZ), major depression (MDD), bipolar disorder (BIP), autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD). Using genetic variants as proxies, our study has identified 137 metabolites linked to the risk of psychiatric disorders, including 2-methoxyacetaminophen sulfate, which affects SCZ (P = 1.7 × 10–5) and 1-docosahexaenoylglycerophosphocholine, which affects ADHD (P = 5.6 × 10–5). Fourteen significant metabolic pathways involved in the 5 psychiatric disorders assessed were also detected, such as glycine, serine, and threonine metabolism for SCZ (P = .0238), Aminoacyl-tRNA biosynthesis for both MDD (P = .0144) and ADHD (P = .0029). Our study provided novel insights into integrating metabolomics with genomics in order to understand the mechanisms underlying the pathogenesis of human diseases.

Download Full-text