| 1. |
- Loza, M. J., et al.
(författare)
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Validated and longitudinally stable asthma phenotypes based on cluster analysis of the ADEPT study
- 2016
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Ingår i: Respiratory Research. - : Springer Nature. - 1465-9921 .- 1465-993X. ; 17:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Asthma is a disease of varying severity and differing disease mechanisms. To date, studies aimed at stratifying asthma into clinically useful phenotypes have produced a number of phenotypes that have yet to be assessed for stability and to be validated in independent cohorts. The aim of this study was to define and validate, for the first time ever, clinically driven asthma phenotypes using two independent, severe asthma cohorts: ADEPT and U-BIOPRED. Methods: Fuzzy partition-around-medoid clustering was performed on pre-specified data from the ADEPT participants (n = 156) and independently on data from a subset of U-BIOPRED asthma participants (n = 82) for whom the same variables were available. Models for cluster classification probabilities were derived and applied to the 12-month longitudinal ADEPT data and to a larger subset of the U-BIOPRED asthma dataset (n = 397). High and low type-2 inflammation phenotypes were defined as high or low Th2 activity, indicated by endobronchial biopsies gene expression changes downstream of IL-4 or IL-13. Results: Four phenotypes were identified in the ADEPT (training) cohort, with distinct clinical and biomarker profiles. Phenotype 1 was "mild, good lung function, early onset", with a low-inflammatory, predominantly Type-2, phenotype. Phenotype 2 had a "moderate, hyper-responsive, eosinophilic" phenotype, with moderate asthma control, mild airflow obstruction and predominant Type-2 inflammation. Phenotype 3 had a "mixed severity, predominantly fixed obstructive, non-eosinophilic and neutrophilic" phenotype, with moderate asthma control and low Type-2 inflammation. Phenotype 4 had a "severe uncontrolled, severe reversible obstruction, mixed granulocytic" phenotype, with moderate Type-2 inflammation. These phenotypes had good longitudinal stability in the ADEPT cohort. They were reproduced and demonstrated high classification probability in two subsets of the U-BIOPRED asthma cohort. Conclusions: Focusing on the biology of the four clinical independently-validated easy-to-assess ADEPT asthma phenotypes will help understanding the unmet need and will aid in developing tailored therapies. Trial registration:NCT01274507(ADEPT), registered October 28, 2010 and NCT01982162(U-BIOPRED), registered October 30, 2013.
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| 2. |
- Li, Chen, et al.
(författare)
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Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length
- 2020
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Ingår i: American Journal of Human Genetics. - : CELL PRESS. - 0002-9297 .- 1537-6605. ; 106:3, s. 389-404
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Tidskriftsartikel (refereegranskat)abstract
- Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1 , PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.
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| 3. |
- Edwards, Alexis C., et al.
(författare)
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Divorce and risk of suicide attempt : A Swedish national study
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Ingår i: Psychological Medicine. - 0033-2917.
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Tidskriftsartikel (refereegranskat)abstract
- Background Prior research has reported an association between divorce and suicide attempt. We aimed to clarify this complex relationship, considering sex differences, temporal factors, and underlying etiologic pathways. Methods We used Swedish longitudinal national registry data for a cohort born 1960-1990 that was registered as married between 1978 and 2018 (N = 1 601 075). We used Cox proportional hazards models to estimate the association between divorce and suicide attempt. To assess whether observed associations were attributable to familial confounders or potentially causal in nature, we conducted co-relative analyses. Results In the overall sample and in sex-stratified analyses, divorce was associated with increased risk of suicide attempt (adjusted hazard ratios [HRs] 1.66-1.77). Risk was highest in the year immediately following divorce (HRs 2.20-2.91) and declined thereafter, but remained elevated 5 or more years later (HRs 1.41-1.51). Divorcees from shorter marriages were at higher risk for suicide attempt than those from longer marriages (HRs 3.33-3.40 and 1.20-1.36, respectively). In general, HRs were higher for divorced females than for divorced males. Co-relative analyses suggested that familial confounders and a causal pathway contribute to the observed associations. Conclusions The association between divorce and risk of suicide attempt is complex, varying as a function of sex and time-related variables. Given evidence that the observed association is due in part to a causal pathway from divorce to suicide attempt, intervention or prevention efforts, such as behavioral therapy, could be most effective early in the divorce process, and in particular among females and those whose marriages were of short duration.
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| 4. |
- Stephenson, Mallory E., et al.
(författare)
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Sibling Alcohol Use Disorder Is Associated With Increased Risk for Suicide Attempt
- 2022
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Ingår i: Clinical Psychological Science. - : SAGE Publications. - 2167-7026 .- 2167-7034. ; 10:2, s. 374-382
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Tidskriftsartikel (refereegranskat)abstract
- The association between having a sibling diagnosed with alcohol use disorder (AUD) and risk for suicide attempt may be attributable to shared genetic liability between AUD and suicidal behavior, effects of environmental exposure to a sibling’s AUD, or both. To distinguish between these alternatives, we conducted a series of Cox regression models using data derived from Swedish population-based registers with national coverage. Among full sibling pairs (656,807 males and 607,096 females), we found that, even after we accounted for the proband’s AUD status, the proband’s risk for suicide attempt was significantly elevated when the proband’s sibling was affected by AUD. Furthermore, the proband’s risk for suicide attempt was consistently higher when the sibling’s AUD registration had occurred more recently. Our findings provide evidence for exposure to sibling AUD as an environmental risk factor for suicide attempt and suggest that clinical outreach may be warranted following a sibling’s diagnosis with AUD.
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| 5. |
- Kendler, Kenneth S., et al.
(författare)
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Does neighborhood alcohol availability moderate the impact of familial liability and marital status on risk for alcohol use disorders? A Swedish national study
- 2020
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Ingår i: Journal of Studies on Alcohol and Drugs. - : Alcohol Research Documentation, Inc.. - 1937-1888 .- 1938-4114. ; 81:6, s. 816-823
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The purpose of this study was to determine whether ease of access to alcohol at the neighborhood level moderates the impact of familial liability and marital status on risk for alcohol use disorder (AUD). Method: Individuals in Sweden were divided into those residing in a neighborhood with (n = 14.1%) versus without (n = 85.9%) an alcohol outlet (bars/nightclubs or government stores). AUD was detected through national medical, legal, and pharmacy registries. Using an additive model predicting AUD registration over 5 years in 1,624,814 individuals, we tested for interactions between the presence of outlets in the individuals’ neighborhoods and familial risk for external-izing syndromes and marital status. Results: In both males and females, we found positive and significant interactions in the prediction of AUD between the presence versus absence of a nearby alcohol outlet with (a) familial risk and (b) single and divorced versus married status. Similar but nonsignificant interactions were seen between nearby outlets and widowed versus married status. These results changed little when all cases with prior AUD were removed from the sample. For males, most of the interaction arose from the proximity of bars/nightclubs, whereas for females the results varied across different kinds of outlets. Conclusions: Environments that provide easy access to alcohol augment the impact of a range of risk factors for AUD, especially familial vulnerability and the reduced social constraints associated with single, divorced, and widowed marital status.
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| 6. |
- Kendler, Kenneth S., et al.
(författare)
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The impact of parenthood on risk of registration for alcohol use disorder in married individuals : A Swedish population-based analysis
- 2019
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Ingår i: Psychological Medicine. - 0033-2917. ; 49:13, s. 2141-2148
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundAlthough being married with children is associated with a reduced rate of alcohol use disorder (AUD), is this finding independent of a marital effect, different in mothers and fathers and potentially causal in effect.MethodsUsing Cox proportional hazards, we examined, in 1 252 237 married individuals, the association between a resident younger and older child and risk for AUD registration in national medical, criminal, and pharmacy registers. Using logistic regression, we analyzed, in 600 219 parents, within-person models comparing risk for AUD prior to first pregnancy v. with young children. We examined whether risk for AUD in 1302 parents after a first spousal AUD registration was reduced by having a young resident child.ResultsCompared with childless married individuals, resident younger children were associated with a reduced risk for AUD in mothers [hazard ratio (HR) 0.36, 95% confidence interval 0.31-0.41] and fathers (HR 0.66, 0.60-0.73). The reduced risk was attenuated but still significant for older children. Within-person models confirmed the protective effect of young children in mothers [odds ratio (OR) 0.49, 0.30-0.80] but yielded inconclusive results in fathers (OR 0.85, 0.58-1.25). After a first spousal registration for AUD, a resident young child was associated with a substantial reduction in risk for mothers and a weaker marginal effect in fathers.ConclusionIn married individuals, resident children are associated with a reduction in basal risk for AUD which is stronger in mothers than fathers and with younger v. older children. This effect is also evident during high-risk periods. In mothers, our results are consistent with a largely causal effect.
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| 7. |
- Salvatore, Jessica E., et al.
(författare)
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Alcohol use disorder and divorce : evidence for a genetic correlation in a population-based Swedish sample
- 2017
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Ingår i: Addiction. - : Wiley. - 0965-2140 .- 1360-0443. ; 112:4, s. 586-593
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Tidskriftsartikel (refereegranskat)abstract
- Aims: We tested the association between alcohol use disorder (AUD) and divorce; estimated the genetic and environmental influences on divorce; estimated how much genetic and environmental influences accounted for covariance between AUD and divorce; and estimated latent genetic and environmental correlations between AUD and divorce. We tested sex differences in these effects. Design: We identified twin and sibling pairs with AUD and divorce information in Swedish national registers. We described the association between AUD and divorce using tetrachorics and used twin and sibling models to estimate genetic and environmental influences on divorce, on the covariance between AUD and divorce and the latent genetic and environmental correlations between AUD and divorce. Setting: Sweden. Participants: A total of 670 836 individuals (53% male) born 1940–1965. Measurements: Life-time measures of AUD and divorce. Findings: AUD and divorce were related strongly (males: rtet = +0.44, 95% CI = 0.43, 0.45; females rtet = +0.37, 95% CI = 0.36, 0.38). Genetic factors accounted for a modest proportion of the variance in divorce (males: 21.3%, 95% CI = 7.6, 28.5; females: 31.0%, 95% CI = 18.8, 37.1). Genetic factors accounted for most of the covariance between AUD and divorce (males: 52.0%, 95% CI = 48.8, 67.9; females: 53.74%, 95% CI = 17.6, 54.5), followed by non-shared environmental factors (males: 45.0%, 95% CI = 37.5, 54.9; females: 41.6%, 95% CI = 40.3, 60.2). Shared environmental factors accounted for a negligible proportion of the covariance (males: 3.0%, 95% CI = −3.0, 13.5; females: 4.75%, 95% CI = 0.0, 6.6). The AUD–divorce genetic correlations were high (males: rA = +0.76, 95% CI = 0.53, 0.90; females +0.52, 95% CI = 0.24, 0.67). The non-shared environmental correlations were modest (males: rE = +0.32, 95% CI = 0.31, 0.40; females: +0.27, 95% CI = 0.27, 0.36). Conclusions: Divorce and alcohol use disorder are correlated strongly in the Swedish population, and the heritability of divorce is consistent with previous studies. Covariation between AUD and divorce results from overlapping genetic and non-shared environmental factors. Latent genetic and non-shared environmental correlations for alcohol use disorder and divorce are high and moderate.
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| 8. |
- Salvatore, Jessica E., et al.
(författare)
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Disentangling Social-Genetic From Rearing-Environment Effects for Alcohol Use Disorder Using Swedish National Data
- 2020
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Ingår i: Psychological Science. - : SAGE Publications. - 0956-7976 .- 1467-9280. ; 31:9, s. 1140-1149
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Tidskriftsartikel (refereegranskat)abstract
- Investigations of social-genetic effects, whereby a social partner’s genotype affects another’s outcomes, can be confounded by the influence of the social partner’s rearing environment. We used marital information on more than 300,000 couples from Swedish national data to disentangle social-genetic from rearing-environment effects for alcohol use disorder (AUD). Using observational and extended-family designs, we found that (a) marriage to a spouse with a predisposition toward AUD (as indexed by a parental history of AUD) increased risk for developing AUD; (b) this increased risk was not explained by socioeconomic status, the spouse’s AUD status, or contact with the spouse’s parents; and (c) this increased risk reflected the psychological consequences of the spouse having grown up with an AUD-affected parent (i.e., a rearing-environment effect) rather than a social-genetic effect. Findings illustrate that a spouse’s rearing-environment exposures may confer risk for AUD.
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| 9. |
- Salvatore, Jessica E., et al.
(författare)
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Family Genetic-Risk Profiles Associated With Divorce
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Ingår i: Clinical Psychological Science. - 2167-7026.
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Tidskriftsartikel (refereegranskat)abstract
- We used Swedish national-register data (N = 2,828,777) to examine divorce and its associated patterns of family genetic-risk scores (FGRSs; personalized measures of genetic risk inferred from diagnoses in relatives) across 10 psychiatric disorders: major depression, anxiety disorders, obsessive compulsive disorder, bipolar disorder, schizophrenia, anorexia nervosa, alcohol use disorder, drug use disorder, attention-deficit/hyperactive disorder, and autism spectrum disorder. Individuals who divorced had elevated FGRSs across all disorders compared with individuals who were stably married or never married. FGRSs for all disorders were higher among divorced females compared with divorced males and among individuals who did not go on to have a stable second marriage compared with individuals who had a stable second marriage and increased as the cumulative number of divorces increased. In summary, genetic predispositions for psychiatric disorders are associated with the propensity to divorce and with several differences as a function of sex, remarriage, and the cumulative number of divorce transitions.
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| 10. |
- Salvatore, Jessica E., et al.
(författare)
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Genetics, the Rearing Environment, and the Intergenerational Transmission of Divorce : A Swedish National Adoption Study
- 2018
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Ingår i: Psychological Science. - : SAGE Publications. - 0956-7976 .- 1467-9280. ; 29:3, s. 370-378
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Tidskriftsartikel (refereegranskat)abstract
- We used classical and extended adoption designs in Swedish registries to disentangle genetic and rearing-environment influences on the intergenerational transmission of divorce. In classical adoption analyses, adoptees (n = 19,715) resembled their biological parents, rather than their adoptive parents, in their history of divorce. In extended adoption analyses, offspring (n = 82,698) resembled their not-lived-with fathers and their lived-with mothers. There was stronger resemblance to lived-with mothers, providing indirect evidence of rearing-environment influences on the intergenerational transmission of divorce. The heritability of divorce assessed across generations was 0.13. We attempted to replicate our findings using within-generation data from adoptive and biological siblings (ns = 8,523–53,097). Adoptees resembled their biological, not adoptive, siblings in their history of divorce. Thus, there was consistent evidence that genetic factors contributed to the intergenerational transmission of divorce but weaker evidence for a rearing-environment effect of divorce. Within-generation data from siblings supported these conclusions.
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| 11. |
- Salvatore, Jessica E., et al.
(författare)
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Origins of spousal cross-concordance for psychiatric disorders : A test of the social stress theory for alcohol use disorder
- 2023
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Ingår i: Psychological Medicine. - 0033-2917. ; 53:10, s. 4772-4779
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Tidskriftsartikel (refereegranskat)abstract
- Background The authors sought to clarify the impact of spousal psychiatric disorders of differing severity [major depression or anxiety disorders (DAD) v. bipolar disorder or nonaffective psychosis (BPN)] on proband risk for alcohol use disorder (AUD) during marriage. Methods In a Swedish cohort (N = 744 628), associations between spousal DAD and BPN and proband AUD were estimated with Cox proportional hazards; associations between parental AUD, proband premarital AUD, and spousal lifetime DAD and BPN were estimated with logistic regression; and whether spousal DAD or BPN causally increased risk for AUD was evaluated with frailty models. Results Spousal premarital DAD, spousal marital-onset DAD, and spousal BPN (premarital or marital-onset) were associated with proband AUD during marriage [hazard ratios (HR) range 1.44-3.72]. Those with a parental or premarital history of AUD (v. without) were more likely to marry a spouse with DAD or BPN (odds ratios 1.22-2.77). Moving from an unaffected first spouse to a DAD-affected second spouse increased AUD risk in males (HR 2.90). Moving from an unaffected first spouse to a BPN-affected second spouse increased AUD risk (HRmales 3.96; HRfemales 5.64). Moving to an unaffected second spouse from a DAD-affected first spouse decreased AUD risk, with stronger evidence in females compared to males (HRmales 0.59; HRfemales 0.28). Conclusions Associations between spousal DAD or BPN and proband AUD reflect both selection and causal effects. Marriage to a BPN-affected spouse has a particularly strong effect on AUD risk, with more modest effects for spousal DAD.
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| 12. |
- Salvatore, Jessica E., et al.
(författare)
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Parental alcohol use disorder and offspring marital outcomes
- 2019
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Ingår i: Addiction. - : Wiley. - 0965-2140. ; 114:1, s. 81-91
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Tidskriftsartikel (refereegranskat)abstract
- Aims: We tested whether parental alcohol use disorder (AUD) predicted adult offspring's likelihood of marriage and marriage to an AUD-affected spouse; whether effects differed as a function of the sex or number of affected parents; and whether they were robust to confounders. Design: Sex-stratified Cox and logistic regression models. Setting: Sweden. Participants: A total of 1 171 070 individuals (51.40% male) born 1965–75. Measurements: Obtained from legal, medical and pharmacy registries. Predictor was parent AUD. Outcomes were marriage and spouse AUD. Adjustments included offspring birth year and AUD; and parental education, marriage, divorce, criminal behavior and drug abuse. Findings: Male and female offspring of AUD-affected parents were more likely to marry at younger ages (< 25), illustrative unadjusted hazard ratio (HR)age 20 = 1.22 (1.17, 1.28) and 1.34 (1.20, 1.39) and were less likely to marry at older ages (> 25), HRage 30 = 0.79 (0.78, 0.81) and 0.82 (0.81, 0.84). Parental AUD was associated with higher odds of having an affected spouse for males and females, odds ratio (OR) = 1.47 (1.38, 1.57) and 1.63 (1.56, 1.70). Effects were more pronounced for those with two versus one AUD-affected parent and adjustments attenuated effects negligibly. Daughters of affected mothers (versus fathers) were more likely to have AUD-affected husbands, OR = 1.68 (1.54, 1.84) versus 1.56 (1.48, 1.64), while there was no difference in sons. Conclusions: In Sweden, parental alcohol use disorder (AUD) is associated with a higher probability of marriage at younger ages, a lower probability of marriage at older ages and a higher likelihood of marriage to an affected spouse compared with no parental AUD. Most of these effects become stronger when the number of AUD-affected parents increases from one to two, and most effects hold after controlling for parents’ socio-economic status, marital history, other externalizing disorders and offspring's own AUD status. Daughters of affected mothers are more likely to have an affected spouse.
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| 13. |
- Salvatore, Jessica E., et al.
(författare)
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Social genetic effects for drug use disorder among spouses
- 2023
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Ingår i: Addiction. - : Wiley. - 0965-2140 .- 1360-0443. ; 118:5, s. 880-889
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Preclinical and human studies suggest that a social partner's genotype may be associated with addiction-related outcomes. This study measured whether spousal genetic makeup is associated with risk of developing drug use disorder (DUD) during marriage and whether the risk associated with a spouse's genotype could be disentangled from potentially confounding rearing environmental effects. Design: Univariable and multivariable logistic regression analyses. Setting: Sweden. Participants: Men and women born between 1960 and 1990 and in opposite-sex first marriages before age 35 (n = 294 748 couples). Measurements: Outcome was DUD diagnosis (inclusive of opioids, sedatives/hypnotics/anxiolytics, cocaine, cannabis, amphetamine and other psychostimulants, hallucinogens, other drugs of abuse and combinations thereof) obtained from legal, medical and pharmacy registries. The focal predictor was family genetic risk scores for DUD (FGRS-DUD), which were inferred from diagnoses in first- through fifth-degree relatives and weighted by degree of genetic sharing. FGRS-DUD were calculated separately for each partner in a couple. Findings: Marriage to a spouse with a high FGRS-DUD was associated with increased risk of developing DUD during marriage, ORmales = 1.68 (95% CI = 1.50, 1.88) and ORfemales = 1.35 (1.16, 1.56), above and beyond the risk associated with one's own FGRS-DUD. The risk associated with a spouse's FGRS-DUD remained statistically significant after covarying for parental education. As indicated by a series of null interaction effects, there was no evidence that the risk associated with a spouse's FGRS-DUD differed depending on whether the spouse was DUD-affected, probands' probable contact with in-laws and whether the spouse was raised by his/her biological parents or in another home. Conclusions: There is relatively robust evidence that a person's risk for developing drug use disorder is associated with the genetic makeup of the person's spouse.
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