Different Characteristics and Heritabilities of Alcohol Use Disorder Classes: A Population-Based Swedish Study.

AIMS: The aims of the present study are to identify alcohol use disorder (AUD) classes among a population-based Swedish sample, determine if these classes differ by variables known to be associated with AUD and determine whether some AUD classes have stronger genetic influences than others. METHODS: A latent class analysis (LCA), based on types of registrations, was conducted on Swedish individuals with an AUD registration born between 1960 and 1990 (N = 184,770). These classes were then validated using demographics; patterns of comorbidity with drug abuse, psychiatric disorders and criminal behavior; and neighborhood-level factors, i.e. peer AUD and neighborhood deprivation. The degree of genetic and environmental influence was also investigated. RESULTS: The best-fit LCA had four classes: (a) outpatient/prescription, characterized by a mix of outpatient medical and prescription registrations, (b) low-frequency inpatient, characterized entirely by inpatient medical registrations, with the majority of individuals having one AUD registration, (c) high-frequency mixed, characterized by a mix of all four registration types, with the majority having four or more registrations and (d) crime, characterized almost entirely by criminal registrations. The highest heritability for both males and females was found for Class 3 (61% and 65%, respectively) and the lowest for Class 1 (20% for both), with shared environmental influences accounting for 10% or less of the variance in all Classes. CONCLUSIONS: Using comprehensive, nationwide registry data, we showed evidence for four distinct, meaningful classes of AUD with varying degrees of heritability.

Geographic proximity is associated with transmission of suicidal behaviour among siblings.

OBJECTIVE: The aim of this study was to clarify the role of 'contagion', or social transmission, in risk of suicidal behaviour (SB) among siblings. METHODS: We followed Swedish sibling pairs until one of them (S1; N = 111,848) was registered for a suicide attempt or completion. We tested the effect of geographic proximity between siblings on risk of a first SB registration of S1's sibling (S2). To control for familial confounding, we conducted complementary analyses of sibling trios (N = 701), comparing risk in different siblings as a function of their respective proximity to S1. RESULTS: The best-fitting model across sibling pairs included an effect of distance between siblings (HR = 0.96, 95% CI = 0.93-0.99). Hazard ratios declined quickly up to 25 km and largely stabilized beyond 150 km. Across all pairs, a larger age difference between siblings was associated with reduced SB risk (HR = 0.96 95% CI = 0.93-0.98). Findings were consistent within the sibling trios. CONCLUSIONS: Consistent with the concept of suicide contagion, risk of suicidal behaviour subsequent to a sibling's suicide completion or attempt is higher as a function of sibling closeness. These findings are robust to potentially confounding familial factors.

Aerobic fitness in late adolescence and the risk of cancer and cancer-associated mortality in adulthood: A prospective nationwide study of 1.2 million Swedish men.

BACKGROUND: The incidence of cancer has steadily risen. It is important to identify modifiable predictors in early life that may decrease cancer risks and mortality. The present study aims to investigate the relationship between aerobic fitness in adolescence and the subsequent risk of cancer and cancer-associated mortality. METHODS: The study included 1 185 439 Swedish men born between 1950 and 1980 that participated in the military conscription (mean age = 18 years). The results from the aerobic fitness test (Wmax) was linked to the risk of cancer and cancer-associated mortality during a 40-years' follow-up using Cox proportional hazards models. A co-sibling design was employed to take familial factors into account. RESULTS: During a mean follow-up of 27 years 15 093 cases of cancer and 4900 cancer-associated mortalities were registered. Higher Wmax (per additional 1 SD) was associated with a decreased risk of cancer at 40 years of follow-up (HR 0.93; 95% CI 0.91-0.96 for cancer and HR 0.82 95% CI 0.76-0.87 for cancer-associated mortality) but not at 5 years of follow-up (HR 1.03; 95% CI 0.99-1.07; and HR 1.04; 95% CI 0.97-1.12). In the co-sibling model the protective effects of high Wmax were increased at 40 years of follow-up for cancer (HR 0.91; 95% CI 0.85-0.98) and cancer-associated mortality (HR 0.78; 95% CI 0.68-0.89). CONCLUSIONS: These findings identify in late adolescence a potentially modifiable predictor of cancer, with higher aerobic fitness associated with a decreased risk of cancer incidence and mortality later in life.

The joint impact of cognitive performance in adolescence and familial cognitive aptitude on risk for major psychiatric disorders: a delineation of four potential pathways to illness.

How do joint measures of premorbid cognitive ability and familial cognitive aptitude (FCA) reflect risk for a diversity of psychiatric and substance use disorders? To address this question, we examined, using Cox models, the predictive effects of school achievement (SA) measured at age 16 and FCA-assessed from SA in siblings and cousins, and educational attainment in parents-on risk for 12 major psychiatric syndromes in 1 140 608 Swedes born 1972-1990. Four developmental patterns emerged. In the first, risk was predicted jointly by low levels of SA and high levels of FCA-that is a level of SA lower than would be predicted from the FCA. This pattern was strongest in autism spectrum disorders and schizophrenia, and weakest in bipolar illness. In these disorders, a pathologic process seems to have caused cognitive functioning to fall substantially short of familial potential. In the second pattern, seen in the internalizing conditions of major depression and anxiety disorders, risk was associated with low SA but was unrelated to FCA. Externalizing disorders-drug abuse and alcohol use disorders-demonstrated the third pattern, in which risk was predicted jointly by low SA and low FCA. The fourth pattern, seen in eating disorders, was directly opposite of that observed in externalizing disorders with risk associated with high SA and high FCA. When measured together, adolescent cognitive ability and FCA identified four developmental patterns leading to diverse psychiatric disorders. The value of cognitive assessments in psychiatric research can be substantially increased by also evaluating familial cognitive potential.

Transmission of alcohol use disorder across three generations: a Swedish National Study.

BACKGROUND: While risk for alcohol use disorder (AUD) is correlated in twins, siblings and parent-offspring pairs, we know little of how this syndrome is transmitted across three generations. METHOD: We examined 685 172 individuals born in Sweden from 1980 to 1990 with four grandparents, and both parents alive in 1980. AUD was assessed in all these individuals from nationwide medical, criminal and pharmacy registries. RESULTS: AUD was stably transmitted across three generations. Parent-child and grandparent-grandchild tetrachoric correlations equaled +0.25 and +0.12, respectively. Grandchild AUD risk did not vary as a function of the sex of the parent or grandparent. However, from grandparents and parents, transmission to grandchildren was stronger in same-sex than opposite-sex pairs. Compared with a grandchild with unaffected parents and grandparents, risk for AUD with a grandparent but no parent affected, a parent but no grandparent affected or both affected increased approximately 70% and 3 and 4-fold, respectively. Grandchildren with ⩾2 grandparents affected had a 40% greater AUD risk than those with only one affected. Tetrachoric correlations for AUD between offspring and great-aunts/uncles, and aunts/uncles equaled +0.06 and +0.13, respectively. CONCLUSIONS: The transmission of AUD in Sweden across three generations is relatively stable. An orderly pattern of resemblance is seen with correlations declining by approximately 50% between first and second, and second and third-degree relatives. While the transmission of risk from affected male and female relatives does not differ, we find consistent evidence for greater resemblance in same-sex v. opposite-sex across generational pairs of relatives.

Prediction of drug abuse recurrence: a Swedish National Study.

BACKGROUND: Relapse from drug abuse (DA) is common, but has rarely been studied in general population samples using a wide range of objective predictors. METHOD: Using nationwide registries, we ascertained 44 523 subjects first registered for DA between the ages of 15 and 40 in 1998 to 2004 and followed for 8 years. We predicted relapse in subjects defined as a second DA registration. We also predicted DA relapse in relative pairs concordant for DA but discordant for relapse. RESULTS: In multivariate regression analyses, the strongest predictors for relapse were prior criminal behavior, male sex, being on social welfare, low school achievement, prior alcoholism, and a high-risk father. A risk index trained from these analyses on random split-halves demonstrated a risk ratio of 1.11 [95% confidence intervals (CIs) 1.10-1.11] per decile and an ROC value of 0.70 (0.69-0.71). Co-relative analyses indicated that a modest proportion of this association was causal, with the remainder arising from familial confounders. A developmental structural equation model revealed a complex interviewing of risk pathways to DA with three key mediational hubs: low educational attainment, early age at first registration, and being on social welfare. CONCLUSIONS: In a general population sample, using objective registry information, DA relapse is substantially predictable. However, the identified risk factors may not be valid targets for interventions because many index familial risk and may not impact causally on probability of relapse. Risk for DA relapse may reflect an inter-weaving, over developmental time, of genetic-temperamental vulnerability, indices of externalizing behaviors and social factors reflecting deprivation.

Social and economic consequences of alcohol use disorder: a longitudinal cohort and co-relative analysis.

BACKGROUND: Although alcohol use disorder (AUD) is associated with future risk for psychosocial dysfunction, the degree to which this arises from a direct causal effect of AUD on functioning v. from correlated risk factors (also known as confounders) is less clearly established. METHOD: AUD was assessed from Swedish medical, criminal and pharmacy registries. In a large general population cohort, using Cox proportional hazard and regression models, we predicted from the onset of AUD four outcomes: early retirement, unemployment, social assistance, and individual income. We then examined the degree to which these associations were attenuated by relevant confounders as well as by the use of discordant cousin, half-sibling, full-sibling, and monozygotic twin pairs. RESULTS: In males, AUD most strongly predicted social assistance [hazard ratio (HR) 8.27, 95% confidence interval (CI) 7.96-8.59], followed by early retirement (HR 5.63, 95% CI 5.53-5.72) and unemployment (HR 2.75, 95% CI 2.65-2.85). For income at age 50, AUD was associated with a decrease in income of 0.24 s.d.s (95% CI -0.25 to -0.23). Results were similar in females. Modest to moderate attenuation of these associations was seen in both sexes after the addition of relevant covariates. These associations were reduced but remained robust in discordant co-relative pairs, including monozygotic twins. CONCLUSIONS: Our results suggest that AUD has a causal impact on a range of measures reflective of psychosocial dysfunction. These findings provide strong support for the drift hypothesis. However, some of the associations between AUD and dysfunction appear to be non-causal and result from shared risk factors, many of which are likely familial.

A developmental model for alcohol use disorders in Swedish men.

BACKGROUND: Alcohol use disorder (AUD) is a classic multifactorial syndrome and it is critical to understand the diversity of the relevant risk factors and how they inter-relate over development. METHOD: We examined 21 risk factors for AUD in four developmental tiers reflecting (i) birth, (ii) childhood and early adolescence, (iii) late adolescence, and (iv) early adulthood in 47 414 Swedish men of whom 3907 (8.2%) were registered for AUD at or after age 25 with a mean length of follow-up of 33.9 (6.6) years. Structural equational model fitting was performed using Mplus. RESULTS: The best-fitting model provided a good fit to the data and explained 23.4% of the variance in AUD. The five strongest predictors were: externalizing behaviors, criminal behavior, father's alcohol consumption, genetic risk, and low educational attainment. Two developmentally early familial/genetic risk factors had substantial direct paths to AUD: father's alcohol consumption and genetic liability. Other broad developmental pathways to risk for AUD were evident: externalizing, psychosocial and internalizing. Overall, the externalizing pathway to AUD was the strongest. However, these pathways were substantially interwoven over time such that risk factors from one domain were commonly predicted by and/or predicted risk factors from the other broad domains of risk. CONCLUSION: AUD in men is an etiologically complex syndrome influenced by familial-genetic, psychosocial, internalizing, and especially externalizing risk factors that act and interact over development and have complicated mediational pathways.

A novel sibling-based design to quantify genetic and shared environmental effects: application to drug abuse, alcohol use disorder and criminal behavior.

BACKGROUND: Twin studies have been criticized for upwardly biased estimates that might contribute to the missing heritability problem. METHOD: We identified, from the general Swedish population born 1960-1990, informative sibships containing a proband, one reared-together full- or half-sibling and a full-, step- or half-sibling with varying degrees of childhood cohabitation with the proband. Estimates of genetic, shared and individual specific environment for drug abuse (DA), alcohol use disorder (AUD) and criminal behavior (CB), assessed from medical, legal or pharmacy registries, were obtained using Mplus. RESULTS: Aggregate estimates of additive genetic effects for DA, AUD and CB obtained separately in males and females varied from 0.46 to 0.73 and agreed with those obtained from monozygotic and dizygotic twins from the same population. Of 54 heritability estimates from individual classes of informative sibling trios (3 syndromes × 9 classes of trios × 2 sexes), heritability estimates from the siblings were lower, tied and higher than those from obtained from twins in 26, one and 27 comparisons, respectively. By contrast, of 54 shared environmental estimates, 33 were lower than those found in twins, one tied and 20 were higher. CONCLUSIONS: With adequate information, human populations can provide many methods for estimating genetic and shared environmental effects. For the three externalizing syndromes examined, concerns that heritability estimates from twin studies are upwardly biased or were not generalizable to more typical kinds of siblings were not supported. Overestimation of heritability from twin studies is not a likely explanation for the missing heritability problem.

Cross-generational transmission from drug abuse in parents to attention-deficit/hyperactivity disorder in children.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) predisposes to drug abuse (DA) and twin studies suggest shared genetic effects. We here seek to determine, using adoption and adoption-like samples, the magnitude of the cross-generational transmission from DA in parents to ADHD in their children and clarify the degree to which this arises from genetic v. rearing effects. METHOD: We ascertained ADHD and DA from multiple Swedish registries. Statistical analysis was performed by Cox and path models. RESULTS: Risk for ADHD was significantly and similarly increased in the offspring of biological mothers and fathers with DA who did v. did not rear their offspring. Risk for ADHD was not elevated in the offspring of adoptive or step-parents with DA. CONCLUSIONS: Cross-generational transmission was observed from DA in parents to ADHD in their children. An analysis of adoptive and adoptive-like parent-offspring relationships suggested that this transmission results from genetic and not from rearing effects.

The rearing environment and risk for drug abuse: a Swedish national high-risk adopted and not adopted co-sibling control study.

BACKGROUND: Although drug abuse (DA) is strongly familial, with important genetic influences, we need to know more about the role of rearing environment in the risk for DA. To address this question, we utilized a high-risk adopted and non-adopted co-sibling control design. METHOD: High-risk offspring had one or more biological parents registered for DA, alcohol use disorders or criminal behavior. Using Swedish registries, we identified 1161 high-risk full-sibships and 3085 high-risk half-sibships containing at least one member who was adopted-away and one member who was not. Registration for DA was via national criminal, medical and pharmacy registers. In Sweden, adoptive families are screened to provide high-quality rearing environment for adoptees. RESULTS: Controlling for parental age at birth and gender (and, in half-siblings, high-risk status of the other parent), risk for DA was substantially lower in the full- and half-siblings who were adopted v. not adopted [hazard ratios and 95% confidence intervals: 0.55 (0.45-0·69) and 0.55 (95% CI 0.48-0.63), respectively]. The protective effect of adoption on risk for DA was significantly stronger in the full- and half-sibling pairs with very high familial liability (two high-risk parents) and significantly weaker when the adoptive family was broken by death or divorce, or contained a high-risk parent. CONCLUSIONS: In both full- and half-sibling pairs, we found replicated evidence that rearing environment strongly impacts on risk for DA. High-quality rearing environments can substantively reduce risk for DA in those at high genetic risk.

Exposure to peer deviance during childhood and risk for drug abuse: a Swedish national co-relative control study.

BACKGROUND: Peer deviance (PD) is associated with risk for drug abuse (DA). Is this association causal? METHOD: DA was recorded in official records. PD was defined as the percentage of peers residing in small communities with future DA registrations. We examined offspring in families whose community PD changed when the offspring was 0-15 years of age and then examined families where cousins or siblings differed in their years of exposure to low or high PD communities. RESULTS: The duration of exposure to PD was strongly associated with future DA. Co-relative analyses for families whose exposure to PD declined suggested that the PD-DA association was largely non-causal. Within full-sibling pairs in such families, the length of exposure to low PD environments was unrelated to risk for DA. By contrast, co-relative analyses in families where exposure to PD increased over time indicated that the PD-DA association was largely causal. In such families, siblings who differed in the duration of their exposure to high PD differed in their risk for subsequent DA. These results were replicated in families whose PD changed because they moved or because of changes in the community in which they resided. CONCLUSIONS: Within families whose social environment is improving over time, the association between PD exposure and offspring DA outcomes is not causal but is due to familial confounding. Within families whose social environment is deteriorating, the PD-DA association seems to be largely causal. Our measure of PD may also reflect broader aspects of the community environment beyond peers.

Attention-deficit/hyperactivity disorder and risk for drug use disorder: a population-based follow-up and co-relative study.

BACKGROUND: Although the association between attention-deficit/hyperactivity disorder (ADHD) and drug use disorder (DUD) is well documented, it is unclear whether it is causal or results from familial confounding. METHOD: In this study we included all 551 164 individuals born in Sweden between 1991 and 1995 and used linked data from multiple nationwide registries to identify those with ADHD prior to age 15 years (1.71%). We used Cox proportional hazards models to investigate the future risk for DUD as a function of an ADHD registration and then compared the results from the entire population with the results from a co-relative design. Using the Swedish Multi-Generation Register, we identified all full-sibling, half-sibling and first-cousin pairs discordant for ADHD. RESULTS: In the population sample, ADHD had a substantially increased risk for future DUD with a hazard ratio (HR) of 3.34 after accounting for gender and parental education. Examining discordant cousin pairs, discordant half-siblings and discordant siblings, those with ADHD had HRs for DUD of 3.09, 2.10 and 2.38 respectively. Controlling for the number of ADHD registrations, ADHD patients with and without stimulant treatment were similarly associated with later DUD risk. CONCLUSIONS: ADHD diagnosed before 15 years of age was strongly related to future risk for DUD. The magnitude of this association was modestly reduced in relative pairs discordant for ADHD, suggesting that the ADHD-DUD association is partly causal and partly a result of familial confounding. We found no evidence to suggest that this association resulted from stimulant treatment.

The association between cannabis abuse and subsequent schizophrenia: a Swedish national co-relative control study.

BACKGROUND: Although cannabis abuse (CA) is known to be associated with schizophrenia, the causal nature of this association is unclear, with prodromal effects complicating its interpretation. METHOD: From Swedish national registry databases, we used a co-relative case-control design with full-sibling, half-sibling and first-cousin comparisons, alongside a general Swedish population sample. Using ICD codes, 5456 individuals with an initial diagnosis of schizophrenia (2000-2010) were matched with five schizophrenia-free controls. We further identified first-cousin, half-sibling and full-sibling pairs discordant for CA and statistically extrapolated results for discordant monozygotic (MZ) twins. RESULTS: Within the general Swedish population, CA was strongly associated with later schizophrenia [odds ratio (OR) 10.44, 95% confidence interval (CI) 8.99-12.11]. This association was substantially attenuated both by increasing temporal delays between CA exposure and schizophrenia diagnosis and by controlling for increasing degrees of familial confounding. Extrapolated discordant MZ pairs suggested that fully controlling for confounding familial factors reduced the association between CA and later schizophrenia to more modest levels (ORs of approximately 3.3 and 1.6 with 3- and 7-year temporal delays respectively). Opiate, sedative, cocaine/stimulant and hallucinogen abuse were also strongly associated with subsequent schizophrenia in the general population. After controlling for familial confounding, only cocaine/stimulant exposure remained associated. CONCLUSIONS: CA has an appreciable causal impact on future risk for schizophrenia. However, population-based estimates of cannabis-schizophrenia co-morbidity substantially overestimate their causal association. Predictions of the cases of schizophrenia that might be prevented by reduced cannabis consumption based on population associations are therefore likely to be considerably overestimated.

A Swedish population-based study of the mechanisms of parent-offspring transmission of criminal behavior.

BACKGROUND: While children of parents with criminal behavior (CB) are at increased risk for CB, we have limited knowledge about the causes of this cross-generational transmission. METHOD: We examined intergenerational continuity in CB in the Swedish population ascertained from the national conviction registers in three family types: intact (n = 21 11 074), 'not-lived-with' (n = 16 53 15 where biological parents never lived with their offspring) and 'step' (n = 1 24 800 offspring) which reflected, respectively, the effects of genes + rearing, genes only and rearing only. We also examined three criminal conviction subtypes: violent CB (VCB), property CB (PCB) and white-collar CB (WCCB). RESULTS: Combined across mothers and fathers, the hazard ratio (HR) for CB in offspring given parental CB was 1.95 in intact, 1.56 in 'not-lived-with' and 1.28 in stepfamilies. In all three family types, all forms of CB in parents (VCB, PCB and WCCB) significantly predicted risk for all forms of CB in offspring. However, VCB in offspring was most strongly predicted by VCB in parents in intact, not-lived-with and stepfamilies. In intact families only, some specific parent-offspring transmission was also seen for WCCB. CONCLUSIONS: Both genetic and environmental factors contribute substantially to parent-offspring resemblance for CB. With respect to criminal subtypes, much of parent-offspring transmission appears to be non-specific. However, specific genetic and environmental risk factors for VCB are transmitted across generations. A limitation of these analyses is that CB was assessed only via official criminal convictions.

The causes of parent-offspring transmission of drug abuse: a Swedish population-based study.

BACKGROUND: While drug abuse (DA) is strongly familial, we still have limited knowledge about the causes of its cross-generational transmission. METHOD: We examined DA ascertained from national registers in offspring of three family types from the Swedish population [intact (n = 2,111,074), 'not-lived-with' (n = 165,315, where biological parents never lived with their offspring) and 'step' (n = 124,800 offspring)], which reflected, respectively, the effects of genes + rearing, genes only and rearing only. We replicated these results in three high-risk co-relative designs. RESULTS: Combined across mothers and fathers, the hazard ratio (HR) for DA in offspring given DA in parents was 3.52 in intact, 2.73 in 'not-lived-with' and 1.79 in stepfamilies. In 968 biological full or half-sibling pairs one of whom was reared by and the other never lived with their parent with DA, the HR for DA was greater in the reared than 'not-lived-with' child (HR 1.57). In 64 offspring pairs of a parent with DA, the HR for DA was greater in a reared biological v. step-parented non-biological child (HR 3.33). In 321 pairs of offspring of a parent with DA one of whom was a not-lived-with biological child and the second a step-parented non-biological child, the HR for DA was greater in the biological v. stepchild (HR 1.80). CONCLUSIONS: Both genetic and environmental factors contribute substantially to parent-offspring resemblance for DA. The general population contains informative family constellations that can complement more traditional adoption designs in clarifying the sources of parent-offspring resemblance.

The causal nature of the association between neighborhood deprivation and drug abuse: a prospective national Swedish co-relative control study.

BACKGROUND: Risk for drug abuse (DA) is strongly associated with neighborhood social deprivation (SD). However, the causal nature of this relationship is unclear. METHOD: Three Swedish population-based cohorts were followed up over 5 years for incident registration of DA in medical, legal or pharmacy records. In each cohort, we examined the SD-DA association, controlling carefully for individual socio-economic status (SES) with multiple measures, in the entire sample and among pairs of first cousins, paternal and maternal half-siblings, full siblings and monozygotic (MZ) twins discordant for SD exposure. The number of informative relative pairs ranged from 6366 to 166,208. RESULTS: In all cohorts, SD was prospectively related to risk for incident DA. In relative pairs discordant for SD exposure, the SD-DA association was similar to that seen in the entire population in cousins, half-siblings, full siblings and MZ twins. Eliminating subjects who were residentially unstable or had DA in the first two follow-up years did not alter this pattern. When divided by age, in the youngest groups, the SD-DA association was weaker in siblings than in the entire population. CONCLUSIONS: Across three cohorts, controlling for individual SES and confounding familial factors, SD prospectively predicted risk for incident DA registration. These results support the hypothesis that the SD-DA association is in part causal and unlikely to result entirely from personal attributes, which both increase risk for DA and cause selection into high SD environments. At least part of the SD-DA association arises because exposure to SD causes an increased risk of DA.

Family history of venous thromboembolism (VTE) and risk of recurrent hospitalization for VTE: a nationwide family study in Sweden.

BACKGROUND: Data concerning the importance of a family history of venous thromboembolism (VTE) for the risk of recurrent VTE are sparse. The aim of this nationwide study was to determine whether a family history of VTE is a risk factor for recurrent hospitalization for unprovoked VTE (deep vein thrombosis of the lower extremities or pulmonary embolism). METHODS: We linked Multigeneration Register data on individuals aged 0-77 years to the Swedish nationwide Hospital Discharge Register data for the period 1987-2009 to compare the risk of hospitalization for unprovoked recurrent VTE among individuals with and without a parental or sibling history of VTE. We calculated hazard ratios (HRs) to determine the familial HR for recurrent hospitalization for VTE. RESULTS AND CONCLUSIONS: The risk of recurrent VTE hospitalization was 1.20 (95% confidence interval [CI] 1.10-1.32) for individuals with affected parents, and 1.30 (95% CI 1.14-1.49) for those with affected siblings. The risk of recurrent VTE hospitalization in individuals with two affected parents was 1.92 (95% CI 1.44-2.58). There was an interaction between age at diagnosis of VTE and a family history of VTE, with a family history having a stronger effect on VTE risk in younger patients. We conclude that a family history of VTE is a modest risk factor for recurrent VTE hospitalization in Sweden.

Clinical features of drug abuse that reflect genetic risk.

BACKGROUND: Drug abuse (DA) is a clinically heterogeneous syndrome. Can we, in a large epidemiological sample, identify clinical features of DA cases that index genetic risk? METHOD: Using registration in medical, legal or pharmacy records, we identified four kinds of relative pairs (n=935,854) starting with a proband with DA: monozygotic co-twins; full siblings; half-siblings; and cousins. Using linear hazard regression, we examined the interaction between three clinical features of DA in the proband and risk for DA in these four relative pairs, ordered by degree of genetic relationship. RESULTS: Increased risk for DA in relatives was robustly predicted by early age at first registration, total number of registrations, and ascertainment in the criminal versus the medical or pharmacy registry. In multivariate models, all three of these variables remained significant and in aggregate strongly predicted DA risk in relatives. The risk for DA in siblings of DA probands in the highest decile of genetic risk predicted by our three indices was more than twice as great as that predicted in siblings of probands in the lowest decile of risk. CONCLUSIONS: In an epidemiological sample, genetic risk for DA can be substantially indexed by simple clinical and historical variables.

Environmental influences on familial resemblance for drug abuse in first-cousin pairs: a Swedish national study.

BACKGROUND: Using three independent methods, prior studies in Swedish sibling pairs indicate that environmental factors contribute substantially to familial aggregation for drug abuse (DA). Could we replicate these results in cousin pairs? METHOD: Using multiple Swedish public databases (1964-2011), we defined DA using medical, legal or pharmacy registry records and examined concordance in full cousin pairs as a function of age differences, younger-older relationships and geographical proximity while growing up. RESULTS: Replicating prior results in siblings, cousin pairs were significantly more similar in their history of DA if they were (i) closer versus more distant in age and (ii) grew up in high versus low geographical proximity to one another. Furthermore, controlling for background factors, having an older cousin with DA conveys a greater risk for DA than having a younger drug-abusing cousin. The greater transmission of DA from older to younger versus younger to older cousin was more prominent in pairs who grew up close to one another. In age difference and geographical proximity analyses, effects were consistently strongest in male-male cousin pairs. In analyses of older → younger versus younger → older transmission, effects were stronger in male-male and male-female than in female-female or female-male relative pairs. CONCLUSIONS: In accord with prior results in siblings, environmental factors contribute substantially to the familial aggregation of DA in cousins and these effects are, in general, stronger in males than in females.