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1.
Am J Hum Genet ; 110(12): 2042-2055, 2023 Dec 07.
Artículo en Inglés | MEDLINE | ID: mdl-37944514

RESUMEN

LDpred2 is a widely used Bayesian method for building polygenic scores (PGSs). LDpred2-auto can infer the two parameters from the LDpred model, the SNP heritability h2 and polygenicity p, so that it does not require an additional validation dataset to choose best-performing parameters. The main aim of this paper is to properly validate the use of LDpred2-auto for inferring multiple genetic parameters. Here, we present a new version of LDpred2-auto that adds an optional third parameter α to its model, for modeling negative selection. We then validate the inference of these three parameters (or two, when using the previous model). We also show that LDpred2-auto provides per-variant probabilities of being causal that are well calibrated and can therefore be used for fine-mapping purposes. We also introduce a formula to infer the out-of-sample predictive performance r2 of the resulting PGS directly from the Gibbs sampler of LDpred2-auto. Finally, we extend the set of HapMap3 variants recommended to use with LDpred2 with 37% more variants to improve the coverage of this set, and we show that this new set of variants captures 12% more heritability and provides 6% more predictive performance, on average, in UK Biobank analyses.


Asunto(s)
Estudio de Asociación del Genoma Completo , Herencia Multifactorial , Humanos , Teorema de Bayes , Estudio de Asociación del Genoma Completo/métodos , Herencia Multifactorial/genética , Polimorfismo de Nucleótido Simple/genética
2.
Am J Hum Genet ; 108(6): 1001-1011, 2021 06 03.
Artículo en Inglés | MEDLINE | ID: mdl-33964208

RESUMEN

The accuracy of polygenic risk scores (PRSs) to predict complex diseases increases with the training sample size. PRSs are generally derived based on summary statistics from large meta-analyses of multiple genome-wide association studies (GWASs). However, it is now common for researchers to have access to large individual-level data as well, such as the UK Biobank data. To the best of our knowledge, it has not yet been explored how best to combine both types of data (summary statistics and individual-level data) to optimize polygenic prediction. The most widely used approach to combine data is the meta-analysis of GWAS summary statistics (meta-GWAS), but we show that it does not always provide the most accurate PRS. Through simulations and using 12 real case-control and quantitative traits from both iPSYCH and UK Biobank along with external GWAS summary statistics, we compare meta-GWAS with two alternative data-combining approaches, stacked clumping and thresholding (SCT) and meta-PRS. We find that, when large individual-level data are available, the linear combination of PRSs (meta-PRS) is both a simple alternative to meta-GWAS and often more accurate.


Asunto(s)
Enfermedad/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Modelos Estadísticos , Herencia Multifactorial , Polimorfismo de Nucleótido Simple , Estudios de Casos y Controles , Humanos , Fenotipo
3.
J Urol ; : 101097JU0000000000004187, 2024 Aug 02.
Artículo en Inglés | MEDLINE | ID: mdl-39093873

RESUMEN

PURPOSE: Childhood incontinence is stigmatized and underprioritized, and a basic understanding of its pathogenesis is missing. Our goal was to identify risk-conferring genetic variants in daytime urinary incontinence (DUI). MATERIALS AND METHODS: We conducted a genome-wide association study in the Danish iPSYCH2015 cohort. Cases (3024) were identified through DUI diagnosis codes and redeemed prescriptions for DUI medication in patients aged 5 to 20 years. Controls (30,240), selected from the same sample, were matched to cases on sex and psychiatric diagnoses, if any, and down-sampled to a 1:10 case:control ratio. Replication was performed in the Icelandic deCODE cohort (5475 cases/287,773 controls). Single-nucleotide polymorphism heritability was calculated using the genome-based restricted maximum likelihood method. Cross-trait genetic correlation was estimated using linkage disequilibrium score regression. Polygenic risk scores generated with LDpred2-auto and BOLT-LMM were assessed for association. RESULTS: Variants on chromosome 6 (rs12210989, odds ratio [OR] 1.24, 95% CI 1.17-1.32, P = 3.21 × 10-12) and 20 (rs4809801, OR 1.18, 95% CI 1.11-1.25, P = 3.66 × 10-8) reached genome-wide significance and implicated the PRDM13 and RIPOR3 genes. Chromosome 6 findings were replicated (P = .024, OR 1.09, 95% CI 1.01-1.16). Liability scale heritability ranged from 10.20% (95% CI 6.40%-14.00%) to 15.30% (95% CI 9.66%-20.94%). DUI and nocturnal enuresis showed positive genetic correlation (rg = 1.28 ± 0.38, P = .0007). DUI was associated with attention-deficit/hyperactivity disorder (OR 1.098, 95% CI 1.046-1.152, P < .0001) and BMI (OR 1.129, 95% CI 1.081-1.178, P < .0001) polygenic risk. CONCLUSIONS: Common genetic variants contribute to the risk of childhood DUI, and genes important in neuronal development and detrusor smooth muscle activity were implicated. These findings may help guide identification of new treatment targets.

4.
Psychol Med ; 54(9): 2073-2086, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38347808

RESUMEN

BACKGROUND: Although several types of risk factors for anorexia nervosa (AN) have been identified, including birth-related factors, somatic, and psychosocial risk factors, their interplay with genetic susceptibility remains unclear. Genetic and epidemiological interplay in AN risk were examined using data from Danish nationwide registers. AN polygenic risk score (PRS) and risk factor associations, confounding from AN PRS and/or parental psychiatric history on the association between the risk factors and AN risk, and interactions between AN PRS and each level of target risk factor on AN risk were estimated. METHODS: Participants were individuals born in Denmark between 1981 and 2008 including nationwide-representative data from the iPSYCH2015, and Danish AN cases from the Anorexia Nervosa Genetics Initiative and Eating Disorder Genetics Initiative cohorts. A total of 7003 individuals with AN and 45 229 individuals without a registered AN diagnosis were included. We included 22 AN risk factors from Danish registers. RESULTS: Risk factors showing association with PRS for AN included urbanicity, parental ages, genitourinary tract infection, and parental socioeconomic factors. Risk factors showed the expected association to AN risk, and this association was only slightly attenuated when adjusted for parental history of psychiatric disorders or/and for the AN PRS. The interaction analyses revealed a differential effect of AN PRS according to the level of the following risk factors: sex, maternal age, genitourinary tract infection, C-section, parental socioeconomic factors and psychiatric history. CONCLUSIONS: Our findings provide evidence for interactions between AN PRS and certain risk-factors, illustrating potential diverse risk pathways to AN diagnosis.


Asunto(s)
Anorexia Nerviosa , Predisposición Genética a la Enfermedad , Herencia Multifactorial , Sistema de Registros , Humanos , Anorexia Nerviosa/epidemiología , Anorexia Nerviosa/genética , Dinamarca/epidemiología , Femenino , Factores de Riesgo , Masculino , Sistema de Registros/estadística & datos numéricos , Adulto , Adolescente , Adulto Joven , Padres/psicología
5.
Psychol Med ; : 1-10, 2024 Oct 14.
Artículo en Inglés | MEDLINE | ID: mdl-39397681

RESUMEN

BACKGROUND: The clinical course of major depressive disorder (MDD) is heterogeneous, and early-onset MDD often has a more severe and complex clinical course. Our goal was to determine whether polygenic scores (PGSs) for psychiatric disorders are associated with treatment trajectories in early-onset MDD treated in secondary care. METHODS: Data were drawn from the iPSYCH2015 sample, which includes all individuals born in Denmark between 1981 and 2008 who were treated in secondary care for depression between 1995 and 2015. We selected unrelated individuals of European ancestry with an MDD diagnosis between ages 10-25 (N = 10577). Seven-year trajectories of hospital contacts for depression were modeled using Latent Class Growth Analysis. Associations between PGS for MDD, bipolar disorder, schizophrenia, ADHD, and anorexia and trajectories of MDD contacts were modeled using multinomial logistic regressions. RESULTS: We identified four trajectory patterns: brief contact (65%), prolonged initial contact (20%), later re-entry (8%), and persistent contact (7%). Relative to the brief contact trajectory, higher PGS for ADHD was associated with a decreased odds of membership in the prolonged initial contact (odds ratio = 1.06, 95% confidence interval = 1.01-1.11) and persistent contact (1.12, 1.03-1.21) trajectories, while PGS-AN was associated with increased odds of membership in the persistent contact trajectory (1.12, 1.03-1.21). CONCLUSIONS: We found significant associations between polygenic liabilities for psychiatric disorders and treatment trajectories in patients with secondary-treated early-onset MDD. These findings help elucidate the relationship between a patient's genetics and their clinical course; however, the effect sizes are small and therefore unlikely to have predictive value in clinical settings.

6.
Psychol Med ; : 1-10, 2024 May 27.
Artículo en Inglés | MEDLINE | ID: mdl-38801094

RESUMEN

BACKGROUND: Psychiatric disorders and type 2 diabetes mellitus (T2DM) are heritable, polygenic, and often comorbid conditions, yet knowledge about their potential shared familial risk is lacking. We used family designs and T2DM polygenic risk score (T2DM-PRS) to investigate the genetic associations between psychiatric disorders and T2DM. METHODS: We linked 659 906 individuals born in Denmark 1990-2000 to their parents, grandparents, and aunts/uncles using population-based registers. We compared rates of T2DM in relatives of children with and without a diagnosis of any or one of 11 specific psychiatric disorders, including neuropsychiatric and neurodevelopmental disorders, using Cox regression. In a genotyped sample (iPSYCH2015) of individuals born 1981-2008 (n = 134 403), we used logistic regression to estimate associations between a T2DM-PRS and these psychiatric disorders. RESULTS: Among 5 235 300 relative pairs, relatives of individuals with a psychiatric disorder had an increased risk for T2DM with stronger associations for closer relatives (parents:hazard ratio = 1.38, 95% confidence interval 1.35-1.42; grandparents: 1.14, 1.13-1.15; and aunts/uncles: 1.19, 1.16-1.22). In the genetic sample, one standard deviation increase in T2DM-PRS was associated with an increased risk for any psychiatric disorder (odds ratio = 1.11, 1.08-1.14). Both familial T2DM and T2DM-PRS were significantly associated with seven of 11 psychiatric disorders, most strongly with attention-deficit/hyperactivity disorder and conduct disorder, and inversely with anorexia nervosa. CONCLUSIONS: Our findings of familial co-aggregation and higher T2DM polygenic liability associated with psychiatric disorders point toward shared familial risk. This suggests that part of the comorbidity is explained by shared familial risks. The underlying mechanisms still remain largely unknown and the contributions of genetics and environment need further investigation.

7.
Twin Res Hum Genet ; 27(2): 69-79, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38644690

RESUMEN

While it is known that vitamin D deficiency is associated with adverse bone outcomes, it remains unclear whether low vitamin D status may increase the risk of a wider range of health outcomes. We had the opportunity to explore the association between common genetic variants associated with both 25 hydroxyvitamin D (25OHD) and the vitamin D binding protein (DBP, encoded by the GC gene) with a comprehensive range of health disorders and laboratory tests in a large academic medical center. We used summary statistics for 25OHD and DBP to generate polygenic scores (PGS) for 66,482 participants with primarily European ancestry and 13,285 participants with primarily African ancestry from the Vanderbilt University Medical Center Biobank (BioVU). We examined the predictive properties of PGS25OHD, and two scores related to DBP concentration with respect to 1322 health-related phenotypes and 315 laboratory-measured phenotypes from electronic health records. In those with European ancestry: (a) the PGS25OHD and PGSDBP scores, and individual SNPs rs4588 and rs7041 were associated with both 25OHD concentration and 1,25 dihydroxyvitamin D concentrations; (b) higher PGS25OHD was associated with decreased concentrations of triglycerides and cholesterol, and reduced risks of vitamin D deficiency, disorders of lipid metabolism, and diabetes. In general, the findings for the African ancestry group were consistent with findings from the European ancestry analyses. Our study confirms the utility of PGS and two key variants within the GC gene (rs4588 and rs7041) to predict the risk of vitamin D deficiency in clinical settings and highlights the shared biology between vitamin D-related genetic pathways a range of health outcomes.


Asunto(s)
Proteína de Unión a Vitamina D , Vitamina D , Humanos , Proteína de Unión a Vitamina D/genética , Vitamina D/sangre , Vitamina D/genética , Vitamina D/análogos & derivados , Femenino , Masculino , Persona de Mediana Edad , Adulto , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Población Blanca/genética , Fenotipo , Anciano , Deficiencia de Vitamina D/genética , Deficiencia de Vitamina D/sangre , Deficiencia de Vitamina D/epidemiología , Herencia Multifactorial/genética
8.
Psychol Med ; 53(11): 5052-5059, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-35811373

RESUMEN

BACKGROUND: Childbirth may be a traumatic experience and vulnerability to posttraumatic stress disorder (PTSD) may increase the risk of postpartum depression (PPD). We investigated whether genetic vulnerability to PTSD as measured by polygenic score (PGS) increases the risk of PPD and whether a predisposition to PTSD in PPD cases exceeds that of major depressive disorder (MDD) outside the postpartum period. METHODS: This case-control study included participants from the iPSYCH2015, a case-cohort of all singletons born in Denmark between 1981 and 2008. Restricting to women born between 1981 and 1997 and excluding women with a first diagnosis other than depression (N = 22 613), 333 were identified with PPD. For each PPD case, 999 representing the background population and 993 with MDD outside the postpartum were matched by calendar year at birth, cohort selection, and age. PTSD PGS was calculated from summary statistics from the Psychiatric Genomics Consortium with LDpred2-auto. Odds ratios (ORs) were estimated using conditional logistic regression adjusted for parental psychiatric history and country of origin, PGS for MDD and age at first birth, and the first 10 principal components. RESULTS: The PTSD PGS was significantly associated with PPD (OR 1.42, 95% CI 1.20-1.68 per standard deviation increase in PTSD PGS) compared to healthy female controls. Genetic PTSD vulnerability in PPD cases did not exceed that of matched female depression cases outside the postpartum period (OR 1.10, 95% CI 0.94-1.30 per standard deviation increase). CONCLUSIONS: Genetic vulnerability to PTSD increased the risk of PPD but did not differ between PPD cases and women with depression at other times.


Asunto(s)
Depresión Posparto , Trastorno Depresivo Mayor , Trastornos por Estrés Postraumático , Recién Nacido , Femenino , Humanos , Depresión Posparto/epidemiología , Depresión Posparto/genética , Depresión Posparto/diagnóstico , Trastorno Depresivo Mayor/epidemiología , Trastorno Depresivo Mayor/genética , Trastorno Depresivo Mayor/psicología , Trastornos por Estrés Postraumático/epidemiología , Trastornos por Estrés Postraumático/genética , Estudios de Casos y Controles , Factores de Riesgo , Periodo Posparto/psicología
9.
Psychol Med ; 53(1): 217-226, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-33949298

RESUMEN

BACKGROUND: In this study, we examined the relationship between polygenic liability for depression and number of stressful life events (SLEs) as risk factors for early-onset depression treated in inpatient, outpatient or emergency room settings at psychiatric hospitals in Denmark. METHODS: Data were drawn from the iPSYCH2012 case-cohort sample, a population-based sample of individuals born in Denmark between 1981 and 2005. The sample included 18 532 individuals who were diagnosed with depression by a psychiatrist by age 31 years, and a comparison group of 20 184 individuals. Information on SLEs was obtained from nationwide registers and operationalized as a time-varying count variable. Hazard ratios and cumulative incidence rates were estimated using Cox regressions. RESULTS: Risk for depression increased by 35% with each standard deviation increase in polygenic liability (p < 0.0001), and 36% (p < 0.0001) with each additional SLE. There was a small interaction between polygenic liability and SLEs (ß = -0.04, p = 0.0009). The probability of being diagnosed with depression in a hospital-based setting between ages 15 and 31 years ranged from 1.5% among males in the lowest quartile of polygenic liability with 0 events by age 15, to 18.8% among females in the highest quartile of polygenic liability with 4+ events by age 15. CONCLUSIONS: These findings suggest that although there is minimal interaction between polygenic liability and SLEs as risk factors for hospital-treated depression, combining information on these two important risk factors could potentially be useful for identifying high-risk individuals.


Asunto(s)
Depresión , Acontecimientos que Cambian la Vida , Masculino , Femenino , Humanos , Lactante , Adulto , Estudios de Cohortes , Factores de Riesgo , Modelos de Riesgos Proporcionales , Estudios de Casos y Controles
10.
Acta Psychiatr Scand ; 2023 Oct 23.
Artículo en Inglés | MEDLINE | ID: mdl-37871908

RESUMEN

BACKGROUND: We quantified relative and absolute risks of postpartum psychiatric episodes (PPE) following risk factors: Young age, past personal or family history of psychiatric disorders, and genetic liability. METHODS: We conducted a register-based study using the iPSYCH2012 case-cohort sample. Exposures were personal history of psychiatric episodes prior to childbirth, being a young mother (giving birth before the age of 21.5 years), having a family history of psychiatric disorders, and a high (highest quartile) polygenic score (PGS) for major depression. PPE was defined within 12 months postpartum by prescription of psychotropic medication or in- and outpatient contact to a psychiatric facility. We included primiparous women born 1981-1999, giving birth before January 1st, 2016. We conducted Cox regression to calculate hazard ratios (HRs) of PPE, absolute risks were calculated using cumulative incidence functions. RESULTS: We included 8174 primiparous women, and the estimated baseline PPE risk was 6.9% (95% CI 6.0%-7.8%, number of PPE cases: 2169). For young mothers with a personal and family history of psychiatric disorders, the absolute risk of PPE was 21.6% (95% CI 15.9%-27.8%). Adding information on high genetic liability to depression, the risk increased to 29.2% (95% CI 21.3%-38.4%) for PPE. CONCLUSIONS: Information on prior personal and family psychiatric episodes as well as age may assist in estimating a personalized risk of PPE. Furthermore, additional information on genetic liability could add even further to this risk assessment.

11.
Brain ; 145(2): 555-568, 2022 04 18.
Artículo en Inglés | MEDLINE | ID: mdl-35022648

RESUMEN

Febrile seizures represent the most common type of pathological brain activity in young children and are influenced by genetic, environmental and developmental factors. In a minority of cases, febrile seizures precede later development of epilepsy. We conducted a genome-wide association study of febrile seizures in 7635 cases and 83 966 controls identifying and replicating seven new loci, all with P < 5 × 10-10. Variants at two loci were functionally related to altered expression of the fever response genes PTGER3 and IL10, and four other loci harboured genes (BSN, ERC2, GABRG2, HERC1) influencing neuronal excitability by regulating neurotransmitter release and binding, vesicular transport or membrane trafficking at the synapse. Four previously reported loci (SCN1A, SCN2A, ANO3 and 12q21.33) were all confirmed. Collectively, the seven novel and four previously reported loci explained 2.8% of the variance in liability to febrile seizures, and the single nucleotide polymorphism heritability based on all common autosomal single nucleotide polymorphisms was 10.8%. GABRG2, SCN1A and SCN2A are well-established epilepsy genes and, overall, we found positive genetic correlations with epilepsies (rg = 0.39, P = 1.68 × 10-4). Further, we found that higher polygenic risk scores for febrile seizures were associated with epilepsy and with history of hospital admission for febrile seizures. Finally, we found that polygenic risk of febrile seizures was lower in febrile seizure patients with neuropsychiatric disease compared to febrile seizure patients in a general population sample. In conclusion, this largest genetic investigation of febrile seizures to date implicates central fever response genes as well as genes affecting neuronal excitability, including several known epilepsy genes. Further functional and genetic studies based on these findings will provide important insights into the complex pathophysiological processes of seizures with and without fever.


Asunto(s)
Epilepsia , Convulsiones Febriles , Anoctaminas/genética , Niño , Preescolar , Epilepsia/genética , Fiebre/complicaciones , Fiebre/genética , Estudio de Asociación del Genoma Completo , Humanos , Canal de Sodio Activado por Voltaje NAV1.1/genética , Convulsiones Febriles/genética
12.
Int J Eat Disord ; 56(9): 1703-1716, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37232007

RESUMEN

OBJECTIVE: To examine sex differences in risk factors for anorexia nervosa (AN). METHOD: This population-based study involved 44,743 individuals (6,239 AN cases including 5,818 females and 421 males, and 38,504 controls including 18,818 females and 19,686 males) born in Denmark between May 1981 and December 2009. Follow-up began on the individual's sixth birthday and ended at AN diagnosis, emigration, death, or December 31, 2016, whichever occurred first. Exposures included socioeconomic status (SES), pregnancy, birth, and early childhood factors based on data from Danish registers, and psychiatric and metabolic polygenic risk scores (PRS) based on genetic data. Hazard ratios were estimated using weighted Cox proportional hazards models stratified by sex (assigned at birth), with AN diagnosis as the outcome. RESULTS: The effects of early life exposures and PRS on AN risk were comparable between females and males. Although we observed some differences in the magnitude and direction of effects, there were no significant interactions between sex and SES, pregnancy, birth, or early childhood exposures. The effects of most PRS on AN risk were highly similar between the sexes. We observed significant sex-specific effects of parental psychiatric history and body mass index PRS, though these effects did not survive corrections for multiple comparisons. CONCLUSIONS: Risk factors for AN are comparable between females and males. Collaboration across countries with large registers is needed to further investigate sex-specific effects of genetic, biological, and environmental exposures on AN risk, including exposures in later childhood and adolescence as well as the additive effects of exposures. PUBLIC SIGNIFICANCE: Sex differences in the prevalence and clinical presentation of AN warrant examination of sex-specific risk factors. This population-based study indicates that the effects of polygenic risk and early life exposures on AN risk are comparable between females and males. Collaboration between countries with large registers is needed to further investigate sex-specific AN risk factors and improve early identification of AN.


Asunto(s)
Anorexia Nerviosa , Embarazo , Recién Nacido , Adolescente , Humanos , Masculino , Femenino , Preescolar , Anorexia Nerviosa/epidemiología , Anorexia Nerviosa/genética , Anorexia Nerviosa/diagnóstico , Caracteres Sexuales , Factores de Riesgo , Padres , Medición de Riesgo
13.
Nord J Psychiatry ; 77(2): 179-187, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-35635301

RESUMEN

BACKGROUND: Poor school performance is linked to higher risks of self-harm. The association might be explained through genetic liabilities for depression or educational attainment. We investigated the association between school performance and self-harm in a population-based sample while assessing the potential influence of polygenic risk scores (PRSs) for depression (PRSMDD) and for educational attainment (PRSEDU). METHOD: We conducted a follow-up study of individuals born 1987-98 and followed from age 18 until 2016. The total sample consisted of a case group (23,779 diagnosed with mental disorders; schizophrenia, bipolar disorder, depression, autism, and attention deficit hyperactivity disorder (ADHD) and a randomly sampled comparison group (n = 10,925). Genome-wide data were obtained from the Neonatal Screening Biobank and information on school performance, family psychiatric history, and socioeconomic status from national administrative registers. RESULTS: Individuals in the top PRSMDD decile were at higher self-harm risk in the case group (IRR: 1.30; 95% CI 1.15-1.46), whereas individuals in the top PRSEDU decile were at lower self-harm risk (IRR: 0.63; 95% CI: 0.55-0.74). Poorer school performance was associated with higher self-harm risk in persons diagnosed with any mental disorder (IRR: 1.69; 95% CI: 1.44-1.99) and among the comparison group (IRR: 7.93; 95% CI: 4.47-15.18). Observed effects of PRSMDD and PRSEDU on self-harm risk were strongest for individuals with poor school performance. CONCLUSION: Associations between PRSMDD and self-harm risk and between PRSEDU and self-harm risk were found. Nevertheless, these polygenic scores seem currently of limited clinical utility for identifying individuals at high self-harm risk.


Asunto(s)
Depresión , Conducta Autodestructiva , Recién Nacido , Humanos , Adolescente , Depresión/epidemiología , Depresión/genética , Estudios de Seguimiento , Escolaridad , Factores de Riesgo , Conducta Autodestructiva/epidemiología , Conducta Autodestructiva/genética , Dinamarca/epidemiología
14.
Acta Psychiatr Scand ; 146(5): 406-419, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-35999619

RESUMEN

OBJECTIVE: To evaluate the influence of extensive genetic and psychosocial confounding on the association between early childhood infection and five major psychiatric disorders METHODS: A case-cohort study including participants from the Danish iPSYCH2012 sample, a case-cohort sample where all cases born between May 1, 1981, and December 31, 2005, diagnosed with attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar affective disorder (BIP), Major Depressive Disorder (MDD) or schizophrenia (SCZ), were identified and pooled with a representative sample (subcohort) of the Danish population. We used Cox proportional hazards regression customized to the case-cohort setup to calculate hazard ratios of outcome with 95% confidence intervals (CIs), following exposure to early childhood infection before the age of 5 years for ADHD and ASD, and before the age of 10 years for BIP, MDD, and SCZ. To evaluate psychosocial confounding we included sex, calendar period, sibling infections, urbanicity, parental socio-economic status, parental mental health information, and polygenic risk scores for all five disorders, as covariates. To estimate how liability for psychiatric disorders measured through the PRS influenced the risk of early childhood infection, we calculated odds ratios (ORs) with 95% CIs, using logistic regression RESULTS: Early childhood infection was associated with ADHD, ASD, MDD, and SCZ with number of childhood infections increasing the hazard. The HR was still significant in the model with full adjustments after 1 infection for ADHD (HR 1.29, 95% CI: 1.19-1.41), ASD (HR 1.28, 95% CI: 1.18-1.40), MDD (HR 1.23, 95% CI: 1.14-1.33), and SCZ (HR 1.21, 95% CI: 1.07-1.36), but not for BIP (HR1.17, 95% CI: 0.96-1.42). Probands exposed to sibling infections, but not own infection had an absolute risk of ADHD, BIP, MDD, and SCZ that closely approached the absolute risk for individuals exposed to own infections. We found evidence of gene-environment correlation with higher PRS of MDD and to some extent SCZ increasing the risk of infections and higher PRS of BIP associated with significantly decreased risk CONCLUSION: Early childhood infection is significantly associated with ADHD, ASD, MDD, and SCZ and not explained by genetic or psychosocial confounding. Although we found evidence of gene-environment correlation, it had minor impact on the results.


Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad , Trastorno del Espectro Autista , Trastorno Bipolar , Trastorno Depresivo Mayor , Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Trastorno por Déficit de Atención con Hiperactividad/epidemiología , Trastorno por Déficit de Atención con Hiperactividad/genética , Trastorno del Espectro Autista/epidemiología , Trastorno del Espectro Autista/genética , Trastorno Bipolar/epidemiología , Trastorno Bipolar/genética , Niño , Preescolar , Estudios de Cohortes , Trastorno Depresivo Mayor/epidemiología , Trastorno Depresivo Mayor/genética , Humanos
15.
Brain Behav Immun ; 89: 433-439, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32735934

RESUMEN

OBJECTIVE: Major depression and asthma frequently co-occur, suggesting shared genetic vulnerability between these two disorders. We aimed to determine whether a higher genetic liability to major depression was associated with increased childhood asthma risk, and if so, whether such an association differed by sex of the child. METHODS: We conducted a population-based cohort study comprising 16,687 singletons born between 1991 and 2005 in Denmark. We calculated the polygenic risk score (PRS) for major depression as a measure of genetic liability based on the summary statistics from the Major Depressive Disorder Psychiatric Genomics Consortium collaboration. The outcome was incident asthma from age 5 to 15 years, identified from the Danish National Patient Registry and the Danish National Prescription Registry. Stratified Cox regression was used to analyze the data. RESULTS: Greater genetic liability to major depression was associated with an increased asthma risk with a hazard ratio (HR) of 1.06 (95% CI: 1.01-1.10) per standard deviation increase in PRS. Children in the highest major depression PRS quartile had a HR for asthma of 1.20 (95% CI: 1.06-1.36), compared with children in the lowest quartile. However, major depression PRS explained only 0.03% of asthma variance (Pseudo-R2). The HRs of asthma by major depression PRS did not differ between boys and girls. CONCLUSION: Our results suggest a shared genetic contribution to major depression and childhood asthma, and there is no evidence of a sex-specific difference in the association.


Asunto(s)
Asma , Trastorno Depresivo Mayor , Adolescente , Asma/epidemiología , Asma/genética , Niño , Preescolar , Estudios de Cohortes , Depresión , Trastorno Depresivo Mayor/genética , Femenino , Humanos , Masculino , Herencia Multifactorial
16.
Psychiatry Res ; 337: 115927, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38696971

RESUMEN

Eating disorders are a group of severe and potentially enduring psychiatric disorders associated with increased mortality. Compared to other severe mental illnesses, they have received relatively limited research attention. Epidemiological studies often only report relative measures despite these being difficult to interpret having limited practical use. The aims of this study were to evaluate the incidence and prevalence of diagnosed anorexia nervosa (AN), bulimia nervosa, and eating disorder not otherwise specified recorded in Danish hospital registers and estimate both relative and absolute measures of subsequent mortality - both all-cause and cause-specific in a general nationwide population of 1,667,374 individuals. In a smaller, genetically informed case-cohort sample, the prediction of polygenic scores for AN, body fat percentage, and body mass index on AN prevalence and severity was estimated. Despite males being less likely to be diagnosed with an eating disorder, those that do have significantly increased rates of mortality. AN prevalence was highest for individuals with high AN and low body fat percentage/body mass index polygenic scores.


Asunto(s)
Trastornos de Alimentación y de la Ingestión de Alimentos , Herencia Multifactorial , Sistema de Registros , Humanos , Dinamarca/epidemiología , Masculino , Femenino , Trastornos de Alimentación y de la Ingestión de Alimentos/epidemiología , Trastornos de Alimentación y de la Ingestión de Alimentos/mortalidad , Trastornos de Alimentación y de la Ingestión de Alimentos/genética , Adulto , Prevalencia , Incidencia , Adolescente , Adulto Joven , Persona de Mediana Edad , Índice de Masa Corporal , Anorexia Nerviosa/epidemiología , Anorexia Nerviosa/mortalidad , Anorexia Nerviosa/genética
17.
medRxiv ; 2024 Sep 08.
Artículo en Inglés | MEDLINE | ID: mdl-39281730

RESUMEN

Objective: Eating disorders (EDs) are serious psychiatric disorders with an estimated 3.3 million healthy life-years lost worldwide yearly. Understanding the course of illness, diagnostic transitions and remission, and their associated genetic correlates could inform both ED etiology and treatment. The authors investigated occurrences of ED transitions and presumed remission and their genetic correlates as captured by polygenic scores (PGSs) in a large Danish register-based cohort. Methods: The sample compromised of 10,565 individuals with a diagnosis of anorexia nervosa (AN), bulimia nervosa (BN), or eating disorder not otherwise specified (EDNOS) with at least two registered hospital contacts between 1995 and 2018. Based on medical records, occurrence of diagnostic transitions and periods of presumed remission were identified. Associations between 422 PGS and diagnostic transitions and presumed remission were evaluated using Cox proportional hazard models. Results: A minority of ED cases (14.1%-23.1%) experienced a diagnostic transition. Presumed remission ranged between 86.9%-89.8%. Higher (one SD increase) PGS for major depressive disorder and multisite chronic pain were positively associated with transitioning from AN to either BN or EDNOS. Higher PGS on a measure of body fat percentage and financial difficulties were positively associated with presumed remission from AN. Higher PGS for mood swings was positively associated with presumed remission from EDNOS whereas higher PGS for health rating showed the opposite. Conclusions: The authors found that most ED patients did not experience diagnostic transitions but were more likely to experience a period of presumed remission. Both diagnostic transitions and presumed remission have significant polygenic component.

18.
Eur Neuropsychopharmacol ; 81: 20-27, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38310717

RESUMEN

Pregnant women on antidepressants must balance potential fetal harm with the relapse risk. While various clinical and sociodemographic factors are known to influence treatment decisions, the impact of genetic factors remains unexplored. We conducted a cohort study among 2,316 women with diagnosed affective disorders who had redeemed antidepressant prescriptions six months before pregnancy, identified from the Danish Integrated Psychiatric Research study. We calculated polygenic risk scores (PGSs) for major depression (MDD), bipolar disorder (BD), and schizophrenia (SCZ) using individual-level genetic data and summary statistics from genome-wide association studies. We retrieved data on sociodemographic and clinical features from national registers. Applying group-based trajectory modeling, we identified four treatment trajectories across pregnancy and postpartum: Continuers (38.2 %), early discontinuers (22.7 %), late discontinuers (23.8 %), and interrupters (15.3 %). All three PGSs were not associated with treatment trajectories; for instance, the relative risk ratio for continuers versus early discontinuers was 0.93 (95 % CI: 0.81-1.06), 0.98 (0.84-1.13), 1.09 (0.95-1.27) for per 1-SD increase in PGS for MDD, BD, and SCZ, respectively. Sociodemographic factors were generally not associated with treatment trajectories, except for the association between primiparity and continuing antidepressant use. Women who received ≥2 classes or a higher dose of antidepressants had a higher probability of being late discontinuers, interrupters, and continuers. The likelihood of continuing antidepressants or restarting antidepressants postpartum increased with the previous antidepressant treatment duration. Our findings indicate that continued antidepressant use during pregnancy is influenced by the severity of the disease rather than genetic predisposition as measured by PGSs.


Asunto(s)
Trastorno Bipolar , Trastorno Depresivo Mayor , Humanos , Femenino , Embarazo , Estudios de Cohortes , Estudio de Asociación del Genoma Completo , Antidepresivos/uso terapéutico , Trastorno Bipolar/tratamiento farmacológico , Trastorno Bipolar/genética , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/genética
19.
Res Sq ; 2024 Jul 17.
Artículo en Inglés | MEDLINE | ID: mdl-39070652

RESUMEN

Eating disorders (EDs) commonly co-occur with other psychiatric and neurodevelopmental disorders including attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD); however, the pattern of family history and genetic overlap among them requires clarification. This study investigated the diagnostic, familial, and genetic associations of EDs with ADHD and ASD. The nationwide population-based cohort study included all individuals born in Denmark, 1981-2008, linked to their siblings and cousins. Cox regression was used to estimate associations between EDs and ADHD or ASD, and mediation analysis was used to assess the effects of intermediate mood or anxiety disorders. Polygenic scores (PGSs) were used to investigate the genetic association between anorexia nervosa (AN) and ADHD or ASD. Significantly increased risk for any ED was observed following an ADHD [hazard ratio = 1.97, 95% confidence interval = 1.75-2.22] or ASD diagnosis [2.82, 2.48-3.19]. Mediation analysis suggested that intermediate mood or anxiety disorders could account for 44-100% of the association between ADHD or ASD and ED. Individuals with a full sibling or maternal halfsibling with ASD had increased risk of AN [1.54, 1.33-1.78; 1.45, 1.08-1.94] compared to those with siblings without ASD. A positive association was found between ASD-PGS and AN risk [1.06, 1.02-1.09]. In this study, positive phenotypic associations between EDs and ADHD or ASD, mediation by mood or anxiety disorder, and a genetic association between ASD-PGS and AN were observed. These findings could guide future research in the development of new treatments that can mitigate the development of EDs among individuals with ADHD or ASD.

20.
Am J Psychiatry ; 180(3): 200-208, 2023 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-36651623

RESUMEN

OBJECTIVE: The authors investigated associations between polygenic liabilities for bipolar disorder, major depression, and schizophrenia and episode polarity among individuals with bipolar disorder. METHODS: The sample consisted of 2,705 individuals diagnosed with bipolar disorder at Danish psychiatric hospitals between January 1995 and March 2017. DNA was obtained from dried blood spots collected at birth as part of routine screening. Polygenic risk scores (PRSs) for bipolar disorder, major depression, and schizophrenia were generated using a meta-PRS method combining internally and externally trained components. Associations between PRS and polarity at first episode, polarity at any episode, and number of episodes with a given polarity were evaluated for each disorder-specific PRS using logistic and negative binominal regressions adjusted for the other two PRSs, age, sex, genotype platform, and five ancestral principal components. RESULTS: PRS for bipolar disorder was positively associated with any manic episodes (odds ratio=1.23, 95% CI=1.09-1.38). PRS for depression was positively associated with any depressive (odds ratio=1.11, 95% CI=1.01-1.23) and mixed (odds ratio=1.15, 95% CI=1.03-1.28) episodes and negatively associated with any manic episodes (odds ratio=0.76, 95% CI=0.69-0.84). PRS for schizophrenia was positively associated with any manic episodes (odds ratio=1.13, 95% CI=1.01-1.27), but only when psychotic symptoms were present (odds ratio for psychotic mania: 1.27, 95% CI=1.05-1.54; odds ratio for nonpsychotic mania: 1.06, 95% CI=0.93-1.20). These patterns were similar for first-episode polarity and for the number of episodes within each pole. CONCLUSIONS: PRSs for bipolar disorder, major depression, and schizophrenia are associated with episode polarity and psychotic symptoms in a congruent manner among individuals with bipolar disorder.


Asunto(s)
Trastorno Bipolar , Trastorno Depresivo Mayor , Trastornos Psicóticos , Esquizofrenia , Recién Nacido , Humanos , Trastorno Bipolar/genética , Manía , Trastornos Psicóticos/genética , Esquizofrenia/genética , Esquizofrenia/diagnóstico , Trastorno Depresivo Mayor/genética
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