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1.
Hum Hered ; : 1-9, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31480066

RESUMO

BACKGROUND: Heritability estimates (including twin and single nucleotide polymorphism [SNP]-based heritability studies) for fibroids have been inconsistent across prior studies ranging between 9 and 69%. These inconsistencies are due to variations in study design and included populations. A major design issue has been lack of imaging confirmation to identify controls, where asymptomatic women without imaging confirmation may be misclassified as controls leading to an attenuation of heritability estimates. To reconcile the differences in prior heritability estimates and the impact of misclassification of controls on heritability, we determined SNP-based heritability and characterized the genetic architecture of pelvic image-confirmed fibroid cases and controls. METHODS: Analyses were performed among women of European American descent using genome-wide SNP data from BioVU, a clinical database composed of DNA linked to de-identified electronic health records. We estimated the genetic variance explained by all SNPs using Genome-Wide Complex Trait Analysis on imputed data. Fibroid cases and controls were identified using a previously reported phenotyping algorithm that required pelvic imaging confirmation. RESULTS: In total, we used 1,067 image-confirmed fibroid cases and 1,042 image-confirmed fibroid controls. The SNP-based heritability estimate for fibroid risk was h2 = 0.33 ± 0.18 (p = 0.040). We investigated the relationship between heritability per chromosome and chromosome length (r2 < 1%), with chromosome 8 explaining the highest proportion of variance for fibroid risk. There was no enrichment for intergenic or genic SNPs for the fibroid SNP-based heritability. Excluding loci previously associated with fibroid risk from genome-wide association study did not attenuate fibroid heritability suggesting that loci associating with fibroid risk are yet to be discovered. CONCLUSIONS: We observed that fibroid SNP-based heritability was higher than the previous estimate using genome-wide SNP data that relied on self-reported outcomes, but within the range of prior twin pair studies. Furthermore, these data support that imprecise phenotyping can significantly affect the ability to estimate heritability using genotype data.

2.
Am J Psychiatry ; : appiajp201918091085, 2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31416338

RESUMO

OBJECTIVE: Individuals at high risk for schizophrenia may benefit from early intervention, but few validated risk predictors are available. Genetic profiling is one approach to risk stratification that has been extensively validated in research cohorts. The authors sought to test the utility of this approach in clinical settings and to evaluate the broader health consequences of high genetic risk for schizophrenia. METHODS: The authors used electronic health records for 106,160 patients from four health care systems to evaluate the penetrance and pleiotropy of genetic risk for schizophrenia. Polygenic risk scores (PRSs) for schizophrenia were calculated from summary statistics and tested for association with 1,359 disease categories, including schizophrenia and psychosis, in phenome-wide association studies. Effects were combined through meta-analysis across sites. RESULTS: PRSs were robustly associated with schizophrenia (odds ratio per standard deviation increase in PRS, 1.55; 95% CI=1.4, 1.7), and patients in the highest risk decile of the PRS distribution had up to 4.6-fold higher odds of schizophrenia compared with those in the bottom decile (95% CI=2.9, 7.3). PRSs were also positively associated with other phenotypes, including anxiety, mood, substance use, neurological, and personality disorders, as well as suicidal behavior, memory loss, and urinary syndromes; they were inversely related to obesity. CONCLUSIONS: The study demonstrates that an available measure of genetic risk for schizophrenia is robustly associated with schizophrenia in health care settings and has pleiotropic effects on related psychiatric disorders as well as other medical syndromes. The results provide an initial indication of the opportunities and limitations that may arise with the future application of PRS testing in health care systems.

4.
Nat Rev Genet ; 20(8): 494, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31253947

RESUMO

In Box 4 of the originally published article, the text describing the Miami plot in part c of the figure contained some minor errors. Specifically, during pre-publication revision of the article, the authors updated the illustrative Miami plot (shown in figure part c) from that of reference 80 (Randall et al. PLoS Genet. (2013)) to a more recent study in reference 82 (Winkler et al. PLoS Genet. (2015)). The box text has now been updated to reflect that change. In paragraph 2, the trait has been updated from "hip circumference adjusted for body mass index" to "waist-to-hip ratio adjusted for body mass index (under 50 years old)" and it has been clarified that female GWAS data are shown on the top half of the plot with male data at the bottom. The original two citations of reference 80 in the Box 4 text have been updated to reference 82. Finally, a typographical artefact was corrected on the Y axis of the Miami plot, whereby the labels '14' and '16' in the top half of the plot we originally both shown as '12'. None of these corrections alter the overall illustrative point that genetic architectures for traits can differ between males and females, which was a conclusion of both reference 80 and reference 82.

5.
Nat Neurosci ; 22(7): 1196, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31168101

RESUMO

Several occurrences of the word 'schizophrenia' have been re-worded as 'liability to schizophrenia' or 'schizophrenia risk', including in the title, which should have been "GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal effect of schizophrenia liability," as well as in Supplementary Figures 1-10 and Supplementary Tables 7-10, to more accurately reflect the findings of the work.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31124312

RESUMO

Psychiatric genetics research is improving our understanding of the biological underpinnings of neurodiversity and mental illness. Using psychiatric genetics in ways that maximize benefits and minimize harms to individuals and society depends largely on how the ethical, legal, and social implications (ELSI) of psychiatric genetics are managed. The International Society of Psychiatric Genetics (ISPG) is the largest international organization dedicated to psychiatric genetics. Given its history, membership, and international reach, we believe the ISPG is well-equipped to contribute to the resolution of these ELSI challenges. As such, we recently created the ISPG Ethics Committee, an interdisciplinary group comprised of psychiatric genetics researchers, clinical geneticists, genetic counselors, mental health professionals, patients, patient advocates, bioethicists, and lawyers. This article highlights key ELSI challenges identified by the ISPG Ethics Committee to be of paramount importance for the ethical translation of psychiatric research into society in three contexts: research settings, clinical settings, and legal proceedings. For each of these arenas, we identify and discuss pressing psychiatric genetics ELSI dilemmas that merit attention and require action. The goal is to increase awareness about psychiatric genetics ELSI issues and encourage dialogue and action among stakeholders.

7.
JAMA Cardiol ; 4(2): 136-143, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30673079

RESUMO

Importance: Thyroid hormone levels are tightly regulated through feedback inhibition by thyrotropin, produced by the pituitary gland. Hyperthyroidism is overwhelmingly due to thyroid disorders and is well recognized to contribute to a wide spectrum of cardiovascular morbidity, particularly the increasingly common arrhythmia atrial fibrillation (AF). Objective: To determine the association between genetically determined thyrotropin levels and AF. Design, Setting, and Participants: This phenome-wide association study scanned 1318 phenotypes associated with a polygenic predictor of thyrotropin levels identified by a previously published genome-wide association study that included participants of European ancestry. North American individuals of European ancestry with longitudinal electronic health records were analyzed from May 2008 to November 2016. Analysis began March 2018. Main Outcomes and Measures: Clinical diagnoses associated with a polygenic predictor of thyrotropin levels. Exposures: Genetically determined thyrotropin levels. Results: Of 37 154 individuals, 19 330 (52%) were men. The thyrotropin polygenic predictor was positively associated with hypothyroidism (odds ratio [OR], 1.10; 95% CI, 1.07-1.14; P = 5 × 10-11) and inversely associated with diagnoses related to hyperthyroidism (OR, 0.64; 95% CI, 0.54-0.74; P = 2 × 10-8 for toxic multinodular goiter). Among nonthyroid associations, the top association was AF/flutter (OR, 0.93; 95% CI, 0.9-0.95; P = 9 × 10-7). When the analyses were repeated excluding 9801 individuals with any diagnoses of a thyroid-related disease, the AF association persisted (OR, 0.91; 95% CI, 0.88-0.95; P = 2.9 × 10-6). To replicate this association, we conducted an inverse-variance weighted average meta-analysis using AF single-nucleotide variant weights from a genome-wide association study of 17 931 AF cases and 115 142 controls. As in the discovery analyses, each SD increase in predicted thyrotropin was associated with a decreased risk of AF (OR, 0.86; 95% CI, 0.79-0.93; P = 4.7 × 10-4). In a set of AF cases (n = 745) and controls (n = 1680) older than 55 years, directly measured thyrotropin levels that fell within the normal range were inversely associated with AF risk (OR, 0.91; 95% CI, 0.83-0.99; P = .04). Conclusions and Relevance: This study suggests a role for genetically determined variation in thyroid function within a physiologically accepted normal range as a risk factor for AF. The clinical decision to treat subclinical thyroid disease should incorporate the risk for AF as antithyroid medications to treat hyperthyroidism may reduce AF risk and thyroid hormone replacement for hypothyroidism may increase AF risk.

8.
Nat Genet ; 51(3): 404-413, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30617256

RESUMO

Alzheimer's disease (AD) is highly heritable and recent studies have identified over 20 disease-associated genomic loci. Yet these only explain a small proportion of the genetic variance, indicating that undiscovered loci remain. Here, we performed a large genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 cases, 383,378 controls). AD-by-proxy, based on parental diagnoses, showed strong genetic correlation with AD (rg = 0.81). Meta-analysis identified 29 risk loci, implicating 215 potential causative genes. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver, and microglia). Gene-set analyses indicate biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomization results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD.


Assuntos
Doença de Alzheimer/genética , Predisposição Genética para Doença/genética , Locos de Características Quantitativas/genética , Adulto , Estudos de Casos e Controles , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Risco , Adulto Jovem
9.
Nat Neurosci ; 22(3): 503, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30622366

RESUMO

The author list was in the wrong order in the HTML version of the original article and in the HTML version of the original correction notice. This has been corrected to show the 23andMe Research Team as the fourth author and Abraham A. Palmer as the last author in both places.

10.
Nat Rev Genet ; 20(3): 173-190, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30581192

RESUMO

Nearly all human complex traits and disease phenotypes exhibit some degree of sex differences, including differences in prevalence, age of onset, severity or disease progression. Until recently, the underlying genetic mechanisms of such sex differences have been largely unexplored. Advances in genomic technologies and analytical approaches are now enabling a deeper investigation into the effect of sex on human health traits. In this Review, we discuss recent insights into the genetic models and mechanisms that lead to sex differences in complex traits. This knowledge is critical for developing deeper insight into the fundamental biology of sex differences and disease processes, thus facilitating precision medicine.


Assuntos
Genoma Humano , Modelos Genéticos , Herança Multifatorial , Medicina de Precisão/métodos , Caracteres Sexuais , Feminino , Humanos , Masculino
11.
Artigo em Inglês | MEDLINE | ID: mdl-30456828

RESUMO

Obsessive-compulsive disorder (OCD) is a highly heritable complex phenotype that demonstrates sex differences in age of onset and clinical presentation, suggesting a possible sex difference in underlying genetic architecture. We present the first genome-wide characterization of the sex-specific genetic architecture of OCD, utilizing the largest set of OCD cases and controls available from the Psychiatric Genomics Consortium. We assessed evidence for several mechanisms that may contribute to sex differences including a sex-dependent liability threshold, the presence of individual sex-specific risk variants on the autosomes and the X chromosome, and sex-specific pleiotropic effects. Furthermore, we tested the hypothesis that genetic heterogeneity between the sexes may obscure associations in a sex-combined genome-wide association study. We observed a strong genetic correlation between male and female OCD and no evidence for a sex-dependent liability threshold model, suggesting that sex-combined analysis does not suffer from widespread loss of power because of genetic heterogeneity between the sexes. While we did not detect any significant sex-specific genome-wide single nucleotide polymorphisms (SNP) associations, we did identify two significant gene-based associations in females: GRID2 and GRP135, which showed no association in males. We observed that the SNPs with sexually differentiated effects showed an enrichment of regulatory variants influencing expression of genes in brain and immune tissues. These findings suggest that future studies with larger sample sizes hold great promise for the identification of sex-specific genetic risk factors for OCD.

12.
Nat Commun ; 9(1): 3522, 2018 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-30166544

RESUMO

Defining the full spectrum of human disease associated with a biomarker is necessary to advance the biomarker into clinical practice. We hypothesize that associating biomarker measurements with electronic health record (EHR) populations based on shared genetic architectures would establish the clinical epidemiology of the biomarker. We use Bayesian sparse linear mixed modeling to calculate SNP weightings for 53 biomarkers from the Atherosclerosis Risk in Communities study. We use the SNP weightings to computed predicted biomarker values in an EHR population and test associations with 1139 diagnoses. Here we report 116 associations meeting a Bonferroni level of significance. A false discovery rate (FDR)-based significance threshold reveals more known and undescribed associations across a broad range of biomarkers, including biometric measures, plasma proteins and metabolites, functional assays, and behaviors. We confirm an inverse association between LDL-cholesterol level and septicemia risk in an independent epidemiological cohort. This approach efficiently discovers biomarker-disease associations.

13.
Mol Psychiatry ; 2018 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-30087453

RESUMO

Anorexia nervosa (AN) and obsessive-compulsive disorder (OCD) are often comorbid and likely to share genetic risk factors. Hence, we examine their shared genetic background using a cross-disorder GWAS meta-analysis of 3495 AN cases, 2688 OCD cases, and 18,013 controls. We confirmed a high genetic correlation between AN and OCD (rg = 0.49 ± 0.13, p = 9.07 × 10-7) and a sizable SNP heritability (SNP h2 = 0.21 ± 0.02) for the cross-disorder phenotype. Although no individual loci reached genome-wide significance, the cross-disorder phenotype showed strong positive genetic correlations with other psychiatric phenotypes (e.g., rg = 0.36 with bipolar disorder and 0.34 with neuroticism) and negative genetic correlations with metabolic phenotypes (e.g., rg = -0.25 with body mass index and -0.20 with triglycerides). Follow-up analyses revealed that although AN and OCD overlap heavily in their shared risk with other psychiatric phenotypes, the relationship with metabolic and anthropometric traits is markedly stronger for AN than for OCD. We further tested whether shared genetic risk for AN/OCD was associated with particular tissue or cell-type gene expression patterns and found that the basal ganglia and medium spiny neurons were most enriched for AN-OCD risk, consistent with neurobiological findings for both disorders. Our results confirm and extend genetic epidemiological findings of shared risk between AN and OCD and suggest that larger GWASs are warranted.

14.
Nat Neurosci ; 21(9): 1161-1170, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30150663

RESUMO

Cannabis use is a heritable trait that has been associated with adverse mental health outcomes. In the largest genome-wide association study (GWAS) for lifetime cannabis use to date (N = 184,765), we identified eight genome-wide significant independent single nucleotide polymorphisms in six regions. All measured genetic variants combined explained 11% of the variance. Gene-based tests revealed 35 significant genes in 16 regions, and S-PrediXcan analyses showed that 21 genes had different expression levels for cannabis users versus nonusers. The strongest finding across the different analyses was CADM2, which has been associated with substance use and risk-taking. Significant genetic correlations were found with 14 of 25 tested substance use and mental health-related traits, including smoking, alcohol use, schizophrenia and risk-taking. Mendelian randomization analysis showed evidence for a causal positive influence of schizophrenia risk on cannabis use. Overall, our study provides new insights into the etiology of cannabis use and its relation with mental health.

15.
Acta Neuropathol ; 136(6): 857-872, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29967939

RESUMO

Cerebrospinal fluid (CSF) levels of amyloid-ß 42 (Aß42) and tau have been evaluated as endophenotypes in Alzheimer's disease (AD) genetic studies. Although there are sex differences in AD risk, sex differences have not been evaluated in genetic studies of AD endophenotypes. We performed sex-stratified and sex interaction genetic analyses of CSF biomarkers to identify sex-specific associations. Data came from a previous genome-wide association study (GWAS) of CSF Aß42 and tau (1527 males, 1509 females). We evaluated sex interactions at previous loci, performed sex-stratified GWAS to identify sex-specific associations, and evaluated sex interactions at sex-specific GWAS loci. We then evaluated sex-specific associations between prefrontal cortex (PFC) gene expression at relevant loci and autopsy measures of plaques and tangles using data from the Religious Orders Study and Rush Memory and Aging Project. In Aß42, we observed sex interactions at one previous and one novel locus: rs316341 within SERPINB1 (p = 0.04) and rs13115400 near LINC00290 (p = 0.002). These loci showed stronger associations among females (ß = - 0.03, p = 4.25 × 10-8; ß = 0.03, p = 3.97 × 10-8) than males (ß = - 0.02, p = 0.009; ß = 0.01, p = 0.20). Higher levels of expression of SERPINB1, SERPINB6, and SERPINB9 in PFC was associated with higher levels of amyloidosis among females (corrected p values < 0.02) but not males (p > 0.38). In total tau, we observed a sex interaction at a previous locus, rs1393060 proximal to GMNC (p = 0.004), driven by a stronger association among females (ß = 0.05, p = 4.57 × 10-10) compared to males (ß = 0.02, p = 0.03). There was also a sex-specific association between rs1393060 and tangle density at autopsy (pfemale = 0.047; pmale = 0.96), and higher levels of expression of two genes within this locus were associated with lower tangle density among females (OSTN p = 0.006; CLDN16 p = 0.002) but not males (p ≥ 0.32). Results suggest a female-specific role for SERPINB1 in amyloidosis and for OSTN and CLDN16 in tau pathology. Sex-specific genetic analyses may improve understanding of AD's genetic architecture.

16.
Nat Neurosci ; 21(7): 1018, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29752479

RESUMO

In the version of this article initially published, the consortium authorship was not presented correctly. The 23andMe Research Team was listed as the last author, rather than the fourth, and a line directing readers to the Supplementary Note for a list of members did appear but was not directly associated with the consortium name. Also, the Supplementary Note description stated that both member names and affiliations were included; in fact, only names are given. Finally, the URL for S-PrediXcan was given in the Methods as https://github.com/hakyimlab/S-PrediXcan; the correct URL is https://github.com/hakyimlab/MetaXcan. The errors have been corrected in the HTML and PDF versions of the article.

17.
Behav Genet ; 48(2): 95-108, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29460079

RESUMO

The American Psychological Association defines gender identity as, "A person's deeply-felt, inherent sense of being a boy, a man, or a male; a girl, a woman, or a female; or an alternative gender (e.g., genderqueer, gender nonconforming, gender neutral) that may or may not correspond to a person's sex assigned at birth or to a person's primary or secondary sex characteristics" (American Psychological Association, Am Psychol 70(9):832-864, 2015). Here we review the evidence that gender identity and related socially defined gender constructs are influenced in part by innate factors including genes. Based on the data reviewed, we hypothesize that gender identity is a multifactorial complex trait with a heritable polygenic component. We argue that increasing the awareness of the biological diversity underlying gender identity development is relevant to all domains of social, medical, and neuroscience research and foundational for reducing health disparities and promoting human-rights protections for gender minorities.


Assuntos
Disforia de Gênero/genética , Identidade de Gênero , Feminino , Humanos , Masculino , Caracteres Sexuais , Comportamento Sexual/psicologia , Pessoas Transgênero/psicologia
18.
Nat Neurosci ; 21(1): 16-18, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29230059

RESUMO

Delay discounting (DD), the tendency to discount the value of delayed versus current rewards, is elevated in a constellation of diseases and behavioral conditions. We performed a genome-wide association study of DD using 23,127 research participants of European ancestry. The most significantly associated single-nucleotide polymorphism was rs6528024 (P = 2.40 × 10-8), which is located in an intron of the gene GPM6B. We also showed that 12% of the variance in DD was accounted for by genotype and that the genetic signature of DD overlapped with attention-deficit/hyperactivity disorder, schizophrenia, major depression, smoking, personality, cognition and body weight.

19.
Diabetes ; 67(1): 155-164, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29084784

RESUMO

Over the past 20 years, a large body of experimental and epidemiologic evidence has linked sleep duration and quality to glucose homeostasis, although the mechanistic pathways remain unclear. The aim of the current study was to determine whether genetic variation influencing both sleep and glucose regulation could underlie their functional relationship. We hypothesized that the genetic regulation of electroencephalographic (EEG) activity during non-rapid eye movement sleep, a highly heritable trait with fingerprint reproducibility, is correlated with the genetic control of metabolic traits including insulin sensitivity and ß-cell function. We tested our hypotheses through univariate and bivariate heritability analyses in a three-generation pedigree with in-depth phenotyping of both sleep EEG and metabolic traits in 48 family members. Our analyses accounted for age, sex, adiposity, and the use of psychoactive medications. In univariate analyses, we found significant heritability for measures of fasting insulin sensitivity and ß-cell function, for time spent in slow-wave sleep, and for EEG spectral power in the delta, theta, and sigma ranges. Bivariate heritability analyses provided the first evidence for a shared genetic control of brain activity during deep sleep and fasting insulin secretion rate.


Assuntos
Encéfalo/metabolismo , Encéfalo/fisiologia , Insulina/metabolismo , Sono/fisiologia , Adiposidade/genética , Adiposidade/fisiologia , Adulto , Glicemia/metabolismo , Eletroencefalografia , Feminino , Teste de Tolerância a Glucose , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Sono/genética
20.
Addict Biol ; 2017 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-29058377

RESUMO

Genetic factors contribute to the risk for developing alcohol use disorder (AUD). In collaboration with the genetics company 23andMe, Inc., we performed a genome-wide association study of the alcohol use disorder identification test (AUDIT), an instrument designed to screen for alcohol misuse over the past year. Our final sample consisted of 20 328 research participants of European ancestry (55.3% females; mean age = 53.8, SD = 16.1) who reported ever using alcohol. Our results showed that the 'chip-heritability' of AUDIT score, when treated as a continuous phenotype, was 12%. No loci reached genome-wide significance. The gene ADH1C, which has been previously implicated in AUD, was among our most significant associations (4.4 × 10-7 ; rs141973904). We also detected a suggestive association on chromosome 1 (2.1 × 10-7 ; rs182344113) near the gene KCNJ9, which has been implicated in mouse models of high ethanol drinking. Using linkage disequilibrium score regression, we identified positive genetic correlations between AUDIT score, high alcohol consumption and cigarette smoking. We also observed an unexpected positive genetic correlation between AUDIT and educational attainment and additional unexpected negative correlations with body mass index/obesity and attention-deficit/hyperactivity disorder. We conclude that conducting a genetic study using responses to an online questionnaire in a population not ascertained for AUD may represent a cost-effective strategy for elucidating aspects of the etiology of AUD.

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