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ImportanceWe know little about the transmission of obsessive-compulsive disorder (OCD) across generations.ObjectiveTo evaluate the sources of parent-offspring transmission of OCD and familial cross-generational association with more typical anxiety disorders.Design, Setting, and ParticipantsThis Swedish population register–based study analyzed data for offspring born in Sweden from 1960 to 1995 from the following 4 family types: intact, not-lived-with biological father, lived-with stepfather, and adoptive. Follow-up occurred on December 31, 2018, and data were analyzed from April 6, 2022, to September 26, 2022.ExposuresThree sources of parent-offspring resemblance: genes plus rearing, genes only, and rearing only.Main Outcomes and MeasuresDiagnoses of OCD, all anxiety disorders, generalized anxiety disorder (GAD), social phobia, and panic disorder were obtained from national inpatient, outpatient, and primary care medical registers. Parent-child resemblance was assessed by tetrachoric correlation (r).ResultsThe offspring population consisted of 2 413 128 individuals; mean (SD) age at follow-up was 40.2 (10.7) years, 1 258 670 individuals (52.2%) were male, and 1 154 458 individuals (47.8%) were female. For each type of parent-child relationship, the best-estimate correlation for OCD for genes plus rearing was 0.19 (95% CI, 0.17 to 0.20); genes only, 0.18 (95% CI, 0.11 to 0.24); and rearing only, 0.04 (95% CI, −0.10 to 0.19). From bivariate adoption analyses, the cross-generational genetic correlations between OCD with anxiety disorder diagnostic categories were estimated as follows: for all anxiety disorders, 0.62 (95% CI, 0.46 to 0.77); GAD, 0.87 (95% CI, 0.53 to 1.00); social phobia, 0.70 (95% CI, 0.31 to 1.00); and panic disorder, 0.47 (95% CI, 0.20 to 0.73).Conclusions and RelevanceThis Swedish population register–based study found that OCD was transmitted from parents to children largely through a genetic relationship, with rearing playing a minor role. Viewed cross-generationally, OCD and anxiety disorders were moderately genetically correlated, with the genetic correlations strongest between OCD and GAD, intermediate for OCD and social phobia, and weakest between OCD and panic disorder. These genetic correlations were modestly attenuated when diagnostic hierarchies were imposed before analysis.

ImportanceSince its inception under Kraepelin in the modern era, diagnostic stability and familial/genetic risk have been among the most important psychiatric nosologic validators.ObjectiveTo assess the interrelationships of family genetic risk score (FGRS) with diagnostic stability or diagnostic change in major depression (MD), bipolar disorder (BD), other nonaffective psychosis (ONAP), and schizophrenia.Design, Setting, and ParticipantsThis longitudinal population-based cohort (N = 4 171 120) included individuals with incident cases of MD (n = 235 095), BD (n = 11 681), ONAP (n = 16 009), and schizophrenia (n = 6312) who had at least 1 further diagnosis of the 4 disorders during follow-up, as assessed from Swedish national medical registries, observed over a mean (SD) of 13.1 (5.9) years until a mean (SD) age of 48.4 (12.3) years. Data were collected from January 1973 to December 2018, and data were analyzed from August to September 2022.ExposuresFGRS for MD, BD, ONAP, and schizophrenia, calculated from morbidity risks for disorders in first-degree through fifth-degree relatives, controlling for cohabitation effects.Main Outcomes and MeasuresFinal diagnostic outcome of MD, BD, ONAP, or schizophrenia.ResultsOf 269 097 included individuals, 173 061 (64.3%) were female, and the mean (SD) age at first registration was 35.1 (11.9) years. Diagnostic stability was highest for MD (214 794 [91.4%]), followed by schizophrenia (4621 [73.2%]), BD (7428 [63.6%]), and ONAP (6738 [42.1%]). The second most common final diagnosis for each of these MD, schizophrenia, BD, and ONAP were BD (15 506 [6.6%]), ONAP (1110 [17.6%]), MD (2681 [23.0%]), and schizophrenia (4401 [27.5%]), respectively. A high FGRS for the incident diagnosis was consistently associated with diagnostic stability, while a high FGRS for the final diagnosis and a low FGRS for the incident diagnosis was associated with diagnostic change. In multivariate models, those in the upper 5% of genetic risk had an odds ratio (OR) of 1.75 or greater for the following diagnostic transition: for MD FGRS, ONAP to MD (OR, 1.91; 95% CI, 1.59-2.29) and schizophrenia to MD (OR, 2.45; 95% CI, 1.64-3.68); for BD FGRS, MD to BD (OR, 2.60; 95% CI, 2.47-2.73), ONAP to BD (OR, 2.16; 95% CI, 1.85-2.52), and schizophrenia to BD (OR, 2.20; 95% CI, 1.39-3.49); for ONAP FGRS, MD to ONAP (OR, 1.80; 95% CI, 1.62-2.02), MD to schizophrenia (OR, 1.95; 95% CI, 1.58-2.41), and BD to schizophrenia (OR, 1.89; 95% CI, 1.39-2.56); and for schizophrenia FGRS, MD to schizophrenia (OR, 1.80; 95% CI, 1.46-2.23), and BD to schizophrenia (OR, 1.75; 95% CI, 1.25-2.45). FGRS profiles for incident cases confirmed at final diagnosis were more homogenous than genetic profiles for those who changed diagnoses.Conclusions and RelevanceIn a large population-based longitudinal cohort, the genetic risk factors for MD, BD, ONAP, and schizophrenia were meaningfully and systematically associated with the diagnostic trajectories of these 4 disorders. Over time, clinical diagnosis and genetic risk profiles became increasingly consilient, thereby providing genetic validation of these diagnostic constructs. Diagnostically unstable incident cases were more genetically heterogeneous than those who were diagnostically stable over time.

Preterm delivery has been associated with future cardiometabolic disorders in women. However, the long-term risks of chronic hypertension associated with preterm delivery and whether such risks are attributable to familial confounding are unclear. Such knowledge is needed to improve long-term risk assessment, clinical monitoring, and cardiovascular prevention strategies in women.To examine the long-term risks of chronic hypertension associated with preterm delivery in a large population-based cohort of women.This national cohort study assessed all 2 195 989 women in Sweden with a singleton delivery from January 1, 1973, to December 31, 2015. Data analyses were conducted from March 8, 2021, to August 20, 2021.Pregnancy duration identified from nationwide birth records.New-onset chronic hypertension identified from primary care, specialty outpatient, and inpatient diagnoses using administrative data. Cox proportional hazards regression was used to compute hazard ratios (HRs) while adjusting for preeclampsia, other hypertensive disorders of pregnancy, and other maternal factors. Cosibling analyses were assessed for potential confounding by shared familial (genetic and/or environmental) factors.In 46.1 million person-years of follow-up, 351 189 of 2 195 989 women (16.0%) were diagnosed with hypertension (mean [SD] age, 55.4 [9.9] years). Within 10 years after delivery, the adjusted HR for hypertension associated with preterm delivery (gestational age37 weeks) was 1.67 (95% CI, 1.61-1.74) and when further stratified was 2.23 (95% CI, 1.98-2.52) for extremely preterm (22-27 weeks of gestation), 1.85 (95% CI, 1.74-1.97) for moderately preterm (28-33 weeks of gestation), 1.55 (95% CI, 1.48-1.63) for late preterm (34-36 weeks of gestation), and 1.26 (95% CI, 1.22-1.30) for early-term (37-38 weeks of gestation) compared with full-term (39-41 weeks of gestation) delivery. These risks decreased but remained significantly elevated at 10 to 19 years (preterm vs full-term delivery: adjusted HR, 1.40; 95% CI, 1.36-1.44), 20 to 29 years (preterm vs full-term delivery: adjusted HR, 1.20; 95% CI, 1.18-1.23), and 30 to 43 years (preterm vs full-term delivery: adjusted HR, 95% CI, 1.12; 1.10-1.14) after delivery. These findings were not explained by shared determinants of preterm delivery and hypertension within families.In this large national cohort study, preterm delivery was associated with significantly higher future risks of chronic hypertension. These associations remained elevated at least 40 years later and were largely independent of other maternal and shared familial factors. Preterm delivery should be recognized as a lifelong risk factor for hypertension in women.

Importance Family and genetic approaches have traditionally been used to evaluate our diagnostic concepts. Using a novel method, the family genetic risk score (FGRS), can we validate the genetic architecture of major affective and psychotic disorders in a national Swedish sample? Objective To determine whether FGRSs, calculated for the entire Swedish population, can elucidate the genetic relationship between major affective and psychotic disorders and clarify the association of genetic risk with important clinical features of disease. Design, Setting, and Participants This cohort study included the native Swedish population born from January 1, 1950, through December 31, 1995, and followed up through December 31, 2017. Data were collected from Swedish population-based primary care, specialist, and hospital registers, including age at first registration for a psychiatric diagnosis and number of registrations for major depression, bipolar disorder, and schizophrenia. Data were analyzed from October 15, 2020, to February 2, 2021. Exposures FGRSs for major depression, bipolar disorder, and schizophrenia calculated from morbidity risks for disorders in first- through fifth-degree relatives, controlling for cohabitation. Main Outcomes and Measures Diagnoses of major depression, bipolar disorder, schizophrenia, schizoaffective disorder, and other nonaffective psychoses (ONAPs), age at registration, and number of registrations for major depression, bipolar disorder, and schizophrenia. Diagnostic conversion of major depression to bipolar disorder and ONAPs to schizophrenia was assessed by Cox proportional hazards regression models. Results The cohort included 4 129 002 individuals (51.4% male) with a mean (SD) age at follow-up of 45.5 (13.4) years. Mean FGRSs for major depression, bipolar disorder, and schizophrenia produced distinct patterns for major depression, bipolar disorder, schizophrenia, schizoaffective disorder, and ONAPs with large separations between disorders. In major depression, bipolar disorder, and schizophrenia, high FGRSs were associated with early age at onset and high rates of recurrence: a high mean FGRS for bipolar disorder was associated with early age at onset (younger than 25 years, 0.11; 95% CI, 0.11-0.12) and higher recurrence (8 or more registrations, 0.11; 95% CI, 0.11-0.12) in major depression. The schizophrenia FGRS was separately associated with psychotic and nonpsychotic forms of major depression (0.10; 95% CI, 0.06-0.14 vs 0.03; 95% CI, 0.02-0.03) and bipolar disorder (0.22; 95% CI, 0.16-0.28 vs 0.11; 95% CI, 0.09-0.12). The bipolar disorder and schizophrenia FGRSs were associated with conversion from major depression to bipolar disorder (eg, hazard ratio, 1.70 [95% CI, 1.63-1.78] for high vs low bipolar FGRS) and ONAP to schizophrenia (eg, hazard ratio, 1.38 [95% CI, 1.27-1.51] for high vs low schizophrenia FGRS). Conclusions and Relevance In this Swedish cohort study, the FGRSs for major depression, bipolar disorder, and schizophrenia for the Swedish population clearly separated major affective and psychotic disorders from each other in a larger and more representative patient sample than previously possible. These findings provide possible validation, from a genetic perspective, for these major diagnostic categories. These results replicated and extended prior observations on more limited samples of the association of FGRS with age at onset, recurrence, psychotic subtypes, and diagnostic conversions.

Importance Information about how risk for bipolar disorder is transmitted across generations and how parental risk for bipolar disorder relates to their children’s risk for schizophrenia and major depression is limited. Objective To evaluate the sources of parent-offspring transmission of bipolar disorder and its familial cross-generational association with schizophrenia and major depression. Design, Setting, and Participants Parents and offspring (born 1960-1990) from 4 family types were ascertained from Swedish national samples: intact (offspring, n = 2 175 259), not-lived-with biological father (n = 152 436), lived-with stepfather (n = 73 785), and adoptive (n = 15 624). Data analysis was conducted from October 28, 2019, to January 8, 2020. Exposures Three sources of parent-offspring resemblance: genes plus rearing, genes only, and rearing only. Main Outcomes and Measures Diagnosis of bipolar disorder, broad schizophrenia (ie, schizophrenia as a 3-level variable: unaffected, nonaffective psychosis, and schizophrenia) and major depression obtained from Swedish national registries. Parent-offspring resemblance was assessed primarily by tetrachoric correlation (ie, correlation of liability) and for key results, odds ratios (ORs) from logistic regression. Cross-generational associations of bipolar disorder with broad schizophrenia and major depression were assessed by their transmission from bipolar disorder in parents and transmission to bipolar disorder in offspring. Results The study population included 2 417 104 individuals of 4 family types (51.8% male and 48.2% female; median age, 41 [range, 25-60] years). For bipolar disorder to bipolar disorder transmission, tetrachoric correlations for 3 types of parent-offspring relationships were statistically homogeneous across family type and mothers and fathers for genes plus rearing (0.25; 95% CI, 0.24-0.26), genes only (0.22; 95% CI, 0.18-0.26), and rearing only (0.07; 95% CI, −0.01 to 0.15). Parallel ORs were 5.20 (95% CI, 4.91-5.50), 3.66 (95% CI, 2.97-4.51), and 1.63 (95% CI, 0.96-2.78). Best-estimate, cross-disorder tetrachoric correlations for 3 types of parent-offspring relationships for bipolar disorder and broad schizophrenia were 0.12 (95% CI, 0.11-0.13) for genes plus rearing, 0.12 (95% CI, 0.09-0.14) for genes only, and −0.03 (95% CI, −0.11 to 0.04) for rearing only, with parallel ORs of 1.95 (95% CI, 1.93-1.97), 2.04 (95% CI, 1.75-2.38), and 0.76 (95% CI, 0.43-1.35). For bipolar disorder and major depression, the parallel tetrachoric correlations were 0.09 (95% CI, 0.07-0.10) for genes plus rearing, 0.04 (95% CI, 0.01-0.07) for genes only, and 0.05 (95% CI, 0.01-0.08) for rearing only; parallel ORs were 1.53 (95% CI, 1.50-1.57), 1.23 (95% CI, 1.13-1.34), and 1.25 (95% CI, 1.09-1.42). Heritability for bipolar disorder was estimated at 0.44 (95% CI, 0.36-0.48). Genetic correlations were estimated at 0.572 (95% CI, 0.560-0.589) between bipolar disorder and broad schizophrenia and 0.302 (95% CI, 0.001-0.523) between bipolar disorder and major depression. Conclusions and Relevance The findings of this study suggest that genes are largely responsible for bipolar disorder transmission across generations, although modest rearing effects are also likely present. Cross-generational transmission between bipolar disorder and broad schizophrenia appears to be entirely genetic with a moderate genetic correlation; for bipolar disorder and major depression, transmission appears to result equally from genes and rearing with a modest genetic correlation.

Importance Breast cancer screening guidelines acknowledge the need for earlier screening for women at increased risk but provide limited guidance for women with a family history of breast cancer. A risk-adapted starting age of screening for relatives of patients with breast cancer may help supplement current screening guidelines. Objective To identify the risk-adapted starting age of breast cancer screening on the basis of a woman’s detailed family history. Design, Setting, and Participants This nationwide cohort study analyzed data recorded in the Swedish family-cancer data sets. All women born from 1932 onward and with at least 1 known first-degree relative (FDR) were included (N = 5 099 172). Data from January 1, 1958, to December 31, 2015, were collected. Data were analyzed from October 1, 2017, to March 31, 2019. Exposures Family history of breast cancer in FDRs and second-degree relatives (SDRs). Main Outcomes and Measures Primary invasive breast cancer diagnosis and the age at which women with different constellations of family history attained the risk level at which breast screening is usually recommended. Results Of the 5 099 172 women included in the study, 118 953 (2.3%) received a diagnosis of primary invasive breast cancer. A total of 102 751 women (86.4%; mean [SD] age at diagnosis, 55.9 [11.1] years) did not have family history of breast cancer in FDRs and SDRs at the time of their diagnosis. Risk-adapted starting age of breast cancer screening varied by number of FDRs and SDRs with breast cancer diagnosis and the age at diagnosis of the FDRs. For example, for screening recommendation at age 50 years for the general population (2.2% 10-year cumulative risk), women with multiple affected FDRs, with the youngest affected relative receiving a diagnosis before age 50 years, reached the benchmark risk level at age 27 years. When the youngest relative received a diagnosis after age 50 years, however, this risk level was attained at age 36 years. Conclusions and Relevance This study identifies possible risk-based starting ages for breast cancer screening based on population-based registers. These results may serve as high-quality evidence to supplement current screening guidelines for relatives of patients with breast cancer.

Preterm birth has been associated with cardiometabolic, respiratory, and neuropsychiatric disorders in adulthood. However, the prevalence of survival without any major comorbidities is unknown.To determine the prevalence of survival without major comorbidities in adulthood among persons born preterm vs full-term.National cohort study of all 2 566 699 persons born in Sweden from January 1, 1973, through December 31, 1997, who had gestational age data and who were followed up for survival and comorbidities through December 31, 2015 (ages 18-43 years).Gestational age at birth.Survival without major comorbidities among persons born extremely preterm (22-27 weeks), very preterm (28-33 weeks), late preterm (34-36 weeks), or early term (37-38 weeks), compared with full-term (39-41 weeks). Comorbidities were defined using the Adolescent and Young Adult Health Outcomes and Patient Experience (AYA HOPE) Comorbidity Index, which includes conditions that commonly manifest in adolescence or young adulthood, including neuropsychiatric disorders; and the Charlson Comorbidity Index (CCI), which includes major chronic disorders predictive of mortality in adulthood. Poisson regression was used to determine prevalence ratios and differences, adjusted for potential confounders.In this study population, 48.6% were female, 5.8% were born preterm, and the median age at end of follow-up was 29.8 years (interquartile range, 12.6 years). Of all persons born preterm, 54.6% were alive with no AYA HOPE comorbidities at the end of follow-up. Further stratified, this prevalence was 22.3% for those born extremely preterm, 48.5% for very preterm, 58.0% for late preterm, 61.2% for early term, and 63.0% for full-term. These prevalences were significantly lower for earlier gestational ages vs full-term (eg, adjusted prevalence ratios: extremely preterm, 0.35 [95% CI, 0.33 to 0.36; P .001]; all preterm, 0.86 [95% CI, 0.85 to 0.86; P .001]; adjusted prevalence differences: extremely preterm, -0.41 [95% CI, -0.42 to -0.40; P .001]; all preterm, -0.09 [95% CI, -0.09 to -0.09; P .001]). Using the CCI, the corresponding prevalences were 73.1% (all preterm), 32.5% (extremely preterm), 66.4% (very preterm), 77.1% (late preterm), 80.4% (early term), and 81.8% (full-term) (adjusted prevalence ratios: extremely preterm, 0.39 [95% CI, 0.38 to 0.41; P .001]; all preterm, 0.89 [95% CI, 0.89 to 0.89; P .001]; adjusted prevalence differences: extremely preterm, -0.50 [95% CI, -0.51 to -0.49; P .001]; all preterm, -0.09 [95% CI, -0.09 to -0.09; P .001]).Among persons born preterm in Sweden between 1973 and 1997, the majority survived to early to mid-adulthood without major comorbidities. However, outcomes were worse for those born extremely preterm.

IMPORTANCE: Preterm birth has previously been associated with increased risks of hypertension and diabetes, but not ischemic heart disease (IHD), in adulthood. The reasons for this lack of association with IHD despite associations with its risk factors have been elusive, but may be associated with methodologic issues, such as survivor bias, in prior studies. OBJECTIVE: To determine whether preterm birth is associated with an increased risk of IHD in adulthood in a large population-based cohort. DESIGN, SETTING, AND PARTICIPANTS: This national, population-based cohort study included all 2 141 709 persons who were born as singleton live births in Sweden during 1973 to 1994. The data were analyzed in September 2018. EXPOSURES: Gestational age at birth, identified from nationwide birth records in the Swedish Birth Registry. MAIN OUTCOMES AND MEASURES: Ischemic heart disease that was identified from nationwide inpatient and outpatient diagnoses through 2015 (maximum age, 43 years). A Cox regression was used to examine gestational age at birth in association with IHD in adulthood while adjusting for other perinatal and maternal factors. Cosibling analyses assessed for potential confounding by unmeasured shared familial factors. RESULTS: Of 2 141 709 participants, 1 041 906 (48.6%) were female and there were 1921 persons (0.09%) who received a diagnosis of IHD in 30.9 million person-years of follow-up. Gestational age at birth was inversely associated with IHD risk in adulthood. At ages 30 to 43 years, adjusted hazard ratios for IHD associated with preterm (gestational age

Importance Low academic achievement (AA) in childhood and adolescence is associated with increased substance use. Empirical evidence, using longitudinal epidemiologic data, may provide support for interventions to improve AA as a means to reduce risk of drug abuse (DA). Objective To clarify the nature of the association between adolescent AA and risk of DA by using instrumental variable and co-relative analysis designs. Design, Setting, and Participants This study, assessing nationwide data from individuals born in Sweden between 1971 and 1982, used instrumental variable and co-relative analyses of the association between AA and DA. The instrument was month of birth. Co-relative analyses were conducted in pairs of cousins (263 222 pairs), full siblings (154 295), and monozygotic twins (1623) discordant for AA, with raw results fitted to a genetic model. The AA-DA association was modeled using Cox regression. Data analysis was conducted from October 2017 to January 2018. Exposures Academic achievement assessed at 16 years of age (for instrumental variable analyses), and estimated discordance in AA in pairs of monozygotic twins (for co-relative analyses). Main Outcomes and Measures Drug abuse registration in national medical, criminal, or pharmacy registries. Results This instrumental variable analysis included 934 462 participants (478 341 males and 456 121 females) with a mean (SD) age of 34.7 (4.3) years at a mean follow-up of 19 years. Earlier month of birth was associated with a linear effect on AA, with the regression coefficient per month equaling −0.0225 SDs (95% CI, −0.0231 to −0.0219). Controlling for AA, month of birth had no association with risk of DA (hazard ratio [HR], 1.000; 95% CI, 0.997-1.004). Lower AA had a significant association with risk of subsequent DA registration (HR per SD, 2.33; 95% CI, 2.30-2.35). Instrumental variable analysis produced a substantial but modestly attenuated association (HR, 2.04; 95% CI, 1.75-2.33). Controlling for modest associations between month of birth and parental educational status and DA risk reduced the association to a HR of 1.92 (95% CI, 1.67-2.22). The genetic model applied to the results of co-relative analyses fitted the observed data well and estimated the AA-DA association in monozygotic twins discordant for AA to equal a HR of 1.79 (95% CI, 1.64-1.92). Conclusions and Relevance Two different methodological approaches with divergent assumptions both produced results consistent with the hypothesis that the significant association observed between AA at 16 years of age and risk of DA into middle adulthood may be causal. These results provide empirical support for efforts to improve AA as a means to reduce risk of DA.

Key Points Question Is a family history of venous thromboembolism associated with postoperative venous thromboembolism and major bleeding in patients with primary hip or knee replacement surgical procedures? Findings In this cohort study of 69 505 Swedish patients, a family history of venous thromboembolism was associated with statistically significant increased venous thromboembolism risk and reduced bleeding risk after hip and knee replacement surgical procedures. The heritability (SE) for postoperative venous thromboembolism was 20% (6%). Meaning Familial and most likely genetic factors appear to affect venous thromboembolism and major bleeding risk following hip and knee replacement surgical procedures., Importance The associations of a family history of venous thromboembolism (FH-VTE) with postoperative venous thromboembolism (VTE) and major bleeding after joint replacement surgical procedures are unknown. Objective To determine the risk of VTE and major bleeding in patients after primary hip or knee replacement surgical procedures. Design, Setting, and Participants Cohort study using nationwide population-based databases of Swedish patients without a history of VTE who underwent joint replacement surgical procedures. Patients who had primary hip or knee replacement surgical procedures between July 1, 2005, and August 31, 2012, were identified. Patients born after 1931 without previous VTE were identified in the Swedish Multi-Generation Register. Only individuals with at least 1 parent and 1 full sibling alive between 1964 and the date for the surgical procedure were included. The data analysis was performed from September 1, 2017, to June 15, 2018. Exposures Family history of VTE in a parent and/or a full sibling before the date of the surgical procedure. Main Outcomes and Measures Venous thromboembolism and major bleeding within 90 days of the surgical procedure. Results Of 69 505 study participants, 37 989 (54.7%) were women, and the median (interquartile range) age at the date of discharge was 65 (59-70) years. A total of 803 of 69 505 (1.2%) patients experienced postoperative VTE and 1285 (1.8%) experienced major bleeding. The cumulative VTE risk for those with FH-VTE was 231 of 15 858 (1.5%) and for those without an FH-VTE was 572 of 53 647 (1.1%) (P, This cohort study uses Swedish national databases to assess major bleeding and venous thromboembolism (VTE) following hip and knee replacement surgical procedures in patients with and without a family history of VTE.

Importance Excess alcohol consumption and alcohol use disorders (AUDs) are associated with substantially increased mortality. Efforts to reduce this toll require an understanding of their causes. Objective To clarify the degree to which the excess mortality associated with AUDs arises (1) from the predispositions of the person who develops AUD (and which would likely be shared by close relatives) and (2) as a direct result of AUD itself. Design, Setting, and Participants A prospective cohort and co-relative design study involving all individuals born in Sweden from 1940 to 1965 who had neither died nor migrated prior to 1973 or age 15 years (N = 2 821 036). They were followed up from January 1, 1973, until December 31, 2010. Alcohol use disorder was assessed from medical, criminal, and pharmacy registries. Half-siblings, full-siblings, and monozygotic twin pairs discordant for AUD were obtained from the Multi-Generation and Twin Register. Main Outcome and Measure Death obtained from the Swedish Death registry. Results Our cohort (1 447 887 males and 1 373 149 females) included 131 895 males and 42 163 females registered with AUD. The mean (SD) age at first AUD registration was 39 (13.4) years. We ascertained 127 347 and 76 325 deaths in the male and female subsamples, respectively. Controlling for sex, educational status, and year of birth, the mortality hazard ratio associated with AUD was 5.83 (95% CI, 5.76-5.90) and varied—with an inverted U -shaped function—by age. Examining the AUD-mortality association in the general population and in relative pairs discordant for AUD exposure demonstrated substantial familial confounding in early to mid-adulthood: the AUD-associated mortality hazard ratio was much lower in discordant close relatives than in the general population. In middle to late adulthood, evidence for familial confounding decreased with increasing evidence for a direct effect of AUD on elevated mortality. In the oldest age group (65-70 years), the mortality hazard ratios were similar across the population and all relative pairs, suggesting that the excess mortality was largely a result of having AUD. Adding years since onset of AUD to the model showed that both increasing age and increasing years of duration of AUD contributed to the reduction of familial confounding in the association between AUD and elevated mortality. Conclusions and Relevance Excess mortality associated with AUD arises both from the predispositions of the person who develops AUD and the direct result of having AUD. The effect of predisposition is more prominent early in the life course and in the early years of AUD. The direct effect of AUD becomes progressively more important later in life and with longer duration of AUD. These results have implications for interventions seeking to reduce the elevated AUD-associated mortality.

Importance Proposal of an innovative approach to clarify the mechanism through which poor cognitive performance in adolescence impacts risk for schizophrenia (SZ). Objective To determine whether the developmental processes that predispose to SZ are better reflected by the observed cognitive performance in adolescence or the deviation of that performance from the individual’s familial cognitive aptitude (FCA). Design, Setting, and Participants A prospective cohort design. Risk for SZ and bipolar illness (BPI) are predicted by school achievement (SA) at age 16 years and IQ at ages 18 to 20 years and the deviation of that performance from an individual’s FCA. Familial cognitive aptitude is calculated from the SA, IQ, and educational attainment in biological relatives. Main Outcomes and Measures Diagnoses of SZ or BPI in the Swedish Hospital Discharge Register and the Swedish Outpatient Register. Results Participants were 996 886 individuals with recorded SA and 106 187 individuals with recorded IQ born in Sweden between January 1, 1972, and December 31, 1990, with sufficient numbers of biological relatives to calculate their FCA. The first cohort is 48.7% female, and the second is all male. Risk for SZ was strongly predicted by the deviation of SA from the FCA (hazard ratio [HR], 0.56; 95% CI, 0.49-0.63) but not with the observed SA (HR, 1.01; 95% CI, 0.91-1.13). Similar results were obtained for IQ (HR, 0.53; 95% CI, 0.37-0.77 for the deviation from the FCA and HR, 1.07; 95% CI, 0.78-1.46 for the observed IQ). After matching SZ and control probands on cognitive performance, the siblings of the SZ probands had SA and IQs that did not differ from population means and were significantly higher in cognitive performance than for the siblings of control probands. Correlations in SA and IQs between the pre-SZ probands and their siblings were significantly lower than those observed between the matched control probands and their siblings. Risk for BPI was more weakly predicted by deviations from the FCA. No differences were found in the SA and IQs of siblings of BPI vs matched control probands. Conclusions and Relevance The neurodevelopmental processes that predispose to SZ are not well reflected by cognitive performance per se but rather are much better indexed by the deviation in cognitive ability from that expected from an individual’s FCA. The lowered cognitive performance in the pre-SZ probands appears to arise from qualitative developmental impairments rather than an unlucky combination of the genetic and environmental risk factors widely distributed within their family.

CONTEXT: Prior research suggests that drug abuse (DA) is strongly influenced by both genetic and familial environmental factors. No large-scale adoption study has previously attempted to verify and integrate these findings. OBJECTIVE: To determine how genetic and environmental factors contribute to the risk for DA. DESIGN: Follow-up in 9 public databases (1961-2009) of adopted children and their biological and adoptive relatives. SETTING: Sweden. PARTICIPANTS: The study included 18 115 adopted children born between 1950 and 1993; 78 079 biological parents and siblings; and 51 208 adoptive parents and siblings. MAIN OUTCOME MEASURES: Drug abuse recorded in medical, legal, or pharmacy registry records. RESULTS: Risk for DA was significantly elevated in the adopted offspring of biological parents with DA (odds ratio, 2.09; 95% CI, 1.66-2.62), in biological full and half siblings of adopted children with DA (odds ratio, 1.84; 95% CI, 1.28-2.64; and odds ratio, 1.41; 95% CI, 1.19-1.67, respectively), and in adoptive siblings of adopted children with DA (odds ratio, 1.95; 95% CI, 1.43-2.65). A genetic risk index (including biological parental or sibling history of DA, criminal activity, and psychiatric or alcohol problems) and an environmental risk index (including adoptive parental history of divorce, death, criminal activity, and alcohol problems, as well as an adoptive sibling history of DA and psychiatric or alcohol problems) both strongly predicted the risk for DA. Including both indices along with sex and age at adoption in a predictive model revealed a significant positive interaction between the genetic and environmental risk indices. CONCLUSIONS: Drug abuse is an etiologically complex syndrome strongly influenced by a diverse set of genetic risk factors reflecting a specific liability to DA, by a vulnerability to other externalizing disorders, and by a range of environmental factors reflecting marital instability, as well as psychopathology and criminal behavior in the adoptive home. Adverse environmental effects on DA are more pathogenic in individuals with high levels of genetic risk. These results should be interpreted in the context of limitations of the diagnosis of DA from registries. (Less)

Importance Alcohol use disorder (AUD) runs strongly in families. It is unclear to what extent the cross-generational transmission of AUD results from genetic vs environmental factors. Objective To determine to what extent genetic and environmental factors contribute to the risk for AUD. Design, Setting, and Participants Follow-up in 8 public data registers of adoptees, their biological and adoptive relatives, and offspring and parents from stepfamilies and not-lived-with families in Sweden. In this cohort study, subtypes of AUD were assessed by latent class analysis. A total of 18 115 adoptees (born 1950-1993) and 171 989 and 107 696 offspring of not-lived-with parents and stepparents, respectively (born 1960-1993). Main Outcomes and Measures Alcohol use disorder recorded in medical, legal, or pharmacy registry records. Results Alcohol use disorder in adoptees was significantly predicted by AUD in biological parents (odds ratio, 1.46; 95% CI, 1.29-1.66) and siblings (odds ratio, 1.94; 95% CI, 1.55-2.44) as well as adoptive parents (odds ratio, 1.40; 95% CI, 1.09-1.80). Genetic and environmental risk indices created from biological and adoptive relatives acted additively on adoptee AUD liability. Results from biological and adoptive relatives were replicated and extended from examinations of, respectively, not-lived-with parents and stepparents. Multivariate models in these families showed that AUD in offspring was significantly predicted by AUD, drug abuse, psychiatric illness, and crime in not-lived-with parents and by AUD, drug abuse, crime, and premature death in stepparents. Latent class analyses of adoptees and offspring of not-lived-with parents with AUDs revealed 3 AUD classes characterized by (1) female preponderance and high rates of psychiatric illness, (2) mild nonrecurrent symptoms, and (3) early-onset recurrence, drug abuse, and crime. These classes had distinct genetic signatures in the patterns of risk for various disorders in their not-lived-with parents and striking differences in the rates of recorded mood disorders. Conclusions and Relevance Parent-offspring transmission of AUD results from both genetic and environmental factors. Genetic risk for AUD reflects both a specific liability to AUD and to other externalizing disorders. Environmental risk reflects features of both parental psychopathology and other aspects of the rearing environment. Alcohol use disorder is a heterogeneous syndrome and meaningful subtypes emerged from latent class analysis, which were validated by patterns of disorders in biological parents and specific psychiatric comorbidities. The general population contains informative family constellations that can complement more traditional adoption designs in clarifying the sources of parent-offspring resemblance.

IMPORTANCE Peer deviance (PD) strongly predicts externalizing psychopathologic conditions but has not been previously assessable in population cohorts. We sought to develop such an index of PD and to clarify its effects on risk of drug abuse (DA). OBJECTIVES To examine how strongly PD increases the risk of DA and whether this community-level liability indicator interacts with key DA risk factors at the individual and family levels. DESIGN, SETTING, AND PARTICIPANTS Studies of future DA registration in 1 401 698 Swedish probands born from January 1, 1970, through December 31, 1985, and their adolescent peers in approximately 9200 small community areas. MAIN OUTCOMES AND MEASURES Drug abuse recorded in medical, legal, or pharmacy registry records. RESULTS Peer deviance was defined as the proportion of individuals born within 5 years of the proband living in the same small community when the proband was 15 years old who eventually were registered for DA. Peer deviance strongly predicted future DA in the proband, with rates of DA in older and male peers more strongly predictive than in younger or female peers. The predictive power of PD was only slightly attenuated by adding measures of community deprivation, collective efficacy, or family socioeconomic status. Probands whose parents were divorced were more sensitive to the pathogenic effects of high PD environments. A robust positive interaction was also seen between genetic risk of DA (indexed by rates of DA in first-, second-, and third-degree relatives) and PD exposure. CONCLUSIONS AND RELEVANCE With sufficient data, PD can be measured in populations and strongly predicts DA. In a nationwide sample, risk factors at the level of the individual (genetic vulnerability), family (parental loss), and community (PD) contribute substantially to risk of DA. Individuals at elevated DA risk because of parental divorce or high genetic liability are more sensitive to the pathogenic effects of PD. Although the effect of our PD measure on DA liability cannot be explained by standard measures of community or family risk, we cannot, with available data, discriminate definitively between the effect of true peer effects and other unmeasured risk factors. (Less)

CONTEXT Drug abuse (DA) strongly runs in families. Does this result solely from genetic factors or does the family environment contribute? OBJECTIVE To determine the familial environmental contribution to the risk for DA. DESIGN Follow-up in 9 public databases (1961-2009) in siblings and spouses. SETTING Sweden. PARTICIPANTS A total of 137 199 sibling pairs and 7561 spousal pairs containing a proband with DA and matched control probands. MAIN OUTCOME MEASURES Drug abuse recorded in medical, legal, or pharmacy registry records. RESULTS In the best-fit model, which contained significant linear, quadratic, and cubic effects, among full sibling pairs containing a proband with DA, the relative risk for DA in the sibling declined from more than 6.0 for siblings born within 2 years of each other to less than 4.5 when born 10 years apart. Controlling for age differences in full sibling pairs, the hazard rate for DA in a sibling when the affected proband was older vs younger was 1.42 (95% CI, 1.31-1.54). In the best-fit model, which contained significant linear, quadratic, and cubic effects, among spousal pairs containing a proband with DA, the relative risk for DA in the spouse declined from more than 25.0 within 1 year of proband DA registration to 6.0 after 5 years. CONCLUSIONS Controlling for genetic effects by examining only full siblings, sibling resemblance for the risk for DA was significantly greater in pairs closer vs more distant in age. Older siblings more strongly transmitted the risk for DA to their younger siblings than vice versa. After one spouse is registered for DA, the other spouse has a large short-lived increase in DA risk. These results support strong familial environmental influences on DA at various life stages. A complete understanding of the familial transmission of DA will require knowledge of how genetic and familial environmental risk factors act and interact over development.

ContextKnowledge about ethnic differences in cardiovascular disease (CVD) risk factors among children and young adults from national samples is limited.ObjectiveTo evaluate ethnic differences in CVD risk factors, the age at which differences were first apparent, and whether differences remained after accounting for socioeconomic status (SES).DesignThird National Health and Nutrition Examination Survey, 1988-1994.SettingEighty-nine mobile examination centers.ParticipantsA total of 2769 black, 2854 Mexican American, and 2063 white (non-Hispanic) children and young adults aged 6 to 24 years.Main Outcome MeasuresEthnicity and household level of education (SES) in relation to body mass index (BMI), percentage of energy from dietary fat, cigarette smoking, systolic blood pressure, glycosylated hemoglobin (HbA1c), and non–high-density lipoprotein cholesterol (non–HDL-C [the difference between total cholesterol and HDL-C]).ResultsThe BMI levels were significantly higher for black and Mexican American girls than for white girls, with ethnic differences evident by the age of 6 to 9 years (a difference of approximately 0.5 BMI units) and widening thereafter (a difference of >2 BMI units among 18- to 24-year-olds). Percentages of energy from dietary fat paralleled these findings and were also significantly higher for black than for white boys. Blood pressure levels were higher for black girls than for white girls in every age group, and glycosylated hemoglobin levels were highest for black and Mexican American girls and boys in every age group. In contrast, smoking prevalence was highest for white girls and boys, especially for those from low-SES homes (77% of young men and 61% of young women, aged 18-24 years, from low-SES homes were current smokers). All ethnic differences remained significant after accounting for SES and age.ConclusionThese findings show strong ethnic differences in CVD risk factors among youths of comparable age and SES from a large national sample. The differences highlight the need for heart disease prevention programs to begin early in childhood and continue throughout young adulthood to reduce the risk of atherosclerosis.