Technological readiness and implementation of genomic-driven precision medicine for complex diseases.

The fields of human genetics and genomics have generated considerable knowledge about the mechanistic basis of many diseases. Genomic approaches to diagnosis, prognostication, prevention and treatment - genomic-driven precision medicine (GDPM) - may help optimize medical practice. Here, we provide a comprehensive review of GDPM of complex diseases across major medical specialties. We focus on technological readiness: how rapidly a test can be implemented into health care. Although these areas of medicine are diverse, key similarities exist across almost all areas. Many medical areas have, within their standards of care, at least one GDPM test for a genetic variant of strong effect that aids the identification/diagnosis of a more homogeneous subset within a larger disease group or identifies a subset with different therapeutic requirements. However, for almost all complex diseases, the majority of patients do not carry established single-gene mutations with large effects. Thus, research is underway that seeks to determine the polygenic basis of many complex diseases. Nevertheless, most complex diseases are caused by the interplay of genetic, behavioural and environmental risk factors, which will likely necessitate models for prediction and diagnosis that incorporate genetic and non-genetic data.

Developments allergy in 2019 through the eyes of Clinical and Experimental Allergy, Part II clinical allergy.

In the second of two linked articles, we describe the development in clinical as described by Clinical & Experimental Allergy and other journals in 2019. Epidemiology, clinical allergy, asthma and rhinitis are all covered. In this article, we described the development in the field of allergy as described by Clinical and Experimental Allergy in 2019. Epidemiology, clinical allergy, asthma and rhinitis are all covered.

Developments allergy in 2019 through the eyes of clinical and experimental allergy, part I mechanisms.

In the first of two linked articles, we describe the development in the mechanisms underlying allergy as described by Clinical & Experimental Allergy and other journals in 2019. Experimental models of allergic disease, basic mechanisms, clinical mechanisms and allergens are all covered.

Antidiabetics, statins and the risk of amyotrophic lateral sclerosis.

BACKGROUND: Medications that are used for treatment of metabolic disorders have been suggested to be associated with the development of amyotrophic lateral sclerosis (ALS). METHODS: To examine the associations of antidiabetics and statins with the subsequent risk of ALS we conducted a population-based nested case-control study of 2475 Swedish residents diagnosed with ALS during July 2006 to December 2013 and 12 375 population controls (five for each ALS case). We extracted information on filled prescriptions of antidiabetics and statins for both cases and controls from the Swedish Prescribed Drug Register during the years before ALS diagnosis. Conditional logistic regression was used to calculate odds ratios (ORs) for the associations of these medications with ALS risk. RESULTS: Patients with ALS were less likely to have been prescribed with antidiabetics compared with controls [OR, 0.76; 95% confidence intervals (CI), 0.65-0.90]. Conversely, statins were not associated with ALS risk overall (OR, 1.08; 95% CI, 0.98-1.19), although a positive association was noted among women (OR, 1.28; 95% CI, 1.10-1.48). The latter association was mostly explained by ALS cases being more likely to have a first prescription of statins during the year before diagnosis compared with controls (OR, 2.54; 95% CI, 1.84-3.49). CONCLUSIONS: The inverse association of antidiabetics with ALS is consistent with the previously reported inverse association between type 2 diabetes and ALS risk. The increase in prescription of statins during the year before ALS diagnosis deserves attention because it might reflect an acceleration of the course of ALS due to statin use.

Developments in the field of clinical allergy in 2018 through the eyes of Clinical and Experimental Allergy, Part II.

In this article, we describe developments in the field of clinical allergy as described by Clinical and Experimental Allergy in 2018; epidemiology, asthma and rhinitis, clinical allergy and allergens are all covered.

Antibiotics use and risk of amyotrophic lateral sclerosis in Sweden.

BACKGROUND AND PURPOSE: Previous animal studies have suggested a disrupted intestinal microbiome in amyotrophic lateral sclerosis (ALS). Due to the known effect of antibiotics on gut microflora, the potential role of antibiotics use on the risk of ALS deserves an investigation. METHODS: A nested case-control study was conducted using several Swedish national registers. In all, 2484 ALS patients diagnosed between 1 July 2006 and 31 December 2013 were included as cases, and five controls per case individually matched to the case by sex, birth year and area of residence were randomly selected from the general Swedish population. Information on antibiotics prescriptions before ALS diagnosis was extracted from the Prescribed Drug Register for both cases and controls. A conditional logistic regression model was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: After accounting for potential diagnostic delay in ALS by excluding all prescriptions within 1 year before diagnosis, any antibiotics use was associated with a higher risk of ALS. The ORs (95% CIs) were 1.06 (0.94-1.19), 1.13 (1.00-1.28) and 1.18 (1.03-1.35) when comparing 1, 2-3 and ≥4 prescriptions to no prescription (P for trend = 0.0069). Similar results were noted for antibiotics used for respiratory infections and urinary tract as well as skin and soft tissue infections. Amongst different individual antibiotics, the risk of ALS was especially increased in relation to more than two prescriptions of beta-lactamase sensitive penicillin (OR 1.28; 95% CI 1.10-1.50). CONCLUSIONS: Use of antibiotics, especially repeated, might be associated with a higher subsequent risk of ALS.

Developments in the field of allergy in 2017 through the eyes of Clinical and Experimental Allergy.

In this article, we described the development in the field of allergy as described by Clinical and Experimental Allergy in 2017. Experimental models of allergic disease, basic mechanisms, clinical mechanisms, allergens, asthma and rhinitis and clinical allergy are all covered.

Artistic creativity and risk for schizophrenia, bipolar disorder and unipolar depression: a Swedish population-based case-control study and sib-pair analysis.

BACKGROUND: Many studies have addressed the question of whether mental disorder is associated with creativity, but high-quality epidemiological evidence has been lacking.AimsTo test for an association between studying a creative subject at high school or university and later mental disorder. METHOD: In a case-control study using linked population-based registries in Sweden (N = 4 454 763), we tested for associations between tertiary education in an artistic field and hospital admission with schizophrenia (N = 20 333), bipolar disorder (N = 28 293) or unipolar depression (N = 148 365). RESULTS: Compared with the general population, individuals with an artistic education had increased odds of developing schizophrenia (odds ratio = 1.90, 95% CI = [1.69; 2.12]) bipolar disorder (odds ratio = 1.62 [1.50; 1.75]) and unipolar depression (odds ratio = 1.39 [1.34; 1.44]. The results remained after adjustment for IQ and other potential confounders. CONCLUSIONS: Students of artistic subjects at university are at increased risk of developing schizophrenia, bipolar disorder and unipolar depression in adulthood.Declaration of interestNone.

The familial aggregation of atopic diseases and depression or anxiety in children.

BACKGROUND: Children with asthma and atopic diseases have an increased risk of depression or anxiety. Each of these diseases has strong genetic and environmental components; therefore, it seems likely that there is a shared liability rather than causative risk. OBJECTIVE: To investigate the existence and nature of familial aggregation for the comorbidity of atopic diseases and depression or anxiety. METHODS: Participants came from the Childhood and Adolescent Twin Study in Sweden (CATSS), n = 14 197. Current and ever asthma, eczema, hay fever and food allergy were reported by parents. Internalizing disorders were identified using validated questionnaires. Familial co-aggregation analysis compared monozygotic (MZ) twins and same-sex dizygotic (DZ) twins for atopic disease in 1 twin with internalizing disorder in the other to test for genetic liability. Several familial liability candidates were also tested including parental education, recent maternal psychological stress, childhood family trauma and parental country of birth. RESULTS: Familial co-aggregation analysis found that if 1 twin had at least 1 current atopic disease the partner twin was at risk of having an internalizing disorder regardless of their own atopic status (adjusted OR 1.22 (95% CI 1.08, 1.37). Similar results were found for each atopic disease ever and current. MZ associations were not higher than DZ associations, suggesting that the liability is not genetic in nature. Including other familial candidates to the models made little difference to effect estimates. CONCLUSIONS AND CLINICAL RELEVANCE: Atopic diseases and depression or anxiety tend to occur together in families; therefore, when treating for 1 disease, the physician should consider comorbidity in both the individual and the individual's siblings. We did not find evidence to support a genetic explanation for comorbidity, and further exploration is needed to disentangle the environmental and epigenetic reasons for familial aggregation.

Prenatal maternal psychosocial stress and offspring's asthma and allergic disease: A systematic review and meta-analysis.

BACKGROUND: Prenatal maternal stress may influence offspring's atopic risk through sustained cortisol secretion resulting from activation of the hypothalamic-pituitary axis (HPA), leading to Th2-biased cell differentiation in the foetus. We undertook a systematic review and meta-analysis investigating the relationship between prenatal maternal psychosocial stress and risk of asthma and allergy in the offspring. METHODS: We searched 11 electronic databases from 1960 to 2016, searched the grey literature and contacted experts in the field. Type of stress indicator included mood disorders, anxiety, exposure to violence, bereavement and socio-economic problems occurring during pregnancy, both objectively and subjectively measured. We included all possible asthma and IgE-mediated allergy outcomes. We conducted random-effects meta-analyses to synthesize the data. RESULTS: We identified 9779 papers of which 30 studies (enrolling >6 million participants) satisfied inclusion criteria. The quality of 25 studies was moderate, 4 were strong, and one was weak. Maternal exposure to any type of stressors was associated with an increased risk of offspring atopic eczema/dermatitis (OR 1.34, 95% CI 1.22-1.47), allergic rhinitis (OR 1.30, 95% CI 1.04-1.62), wheeze (OR 1.34, 95% CI 1.16-1.54) and asthma (OR 1.15, 95% CI 1.04-1.27). Exposure to anxiety and depression had strongest effect compared to other stressors. Exposure during the third trimester had the greatest impact compared to first and second trimesters. The increased risk was stronger for early-onset and persistent than for late-onset wheeze. Bereavement of a child (HR 1.28, 95% CI 1.10-1.48) or a spouse (HR 1.40, 95% CI 1.03-1.90) increased the risk of offspring asthma. CONCLUSIONS: Exposure to prenatal maternal psychosocial stress was associated with increased risk, albeit modestly, of asthma and allergy in the offspring. The pronounced risk during the third trimester may represent cumulative stress exposure throughout pregnancy rather than trimester-specific effect. Our findings may represent a causal effect or a result of inherent biases in studies, particularly residual confounding.

Perinatal risk factors in Tourette's and chronic tic disorders: a total population sibling comparison study.

Adverse perinatal events may increase the risk of Tourette's and chronic tic disorders (TD/CTD), but previous studies have been unable to control for unmeasured environmental and genetic confounding. We aimed to prospectively investigate potential perinatal risk factors for TD/CTD, taking unmeasured factors shared between full siblings into account. A population-based birth cohort, consisting of all singletons born in Sweden in 1973-2003, was followed until December 2013. A total of 3 026 861 individuals were identified, 5597 of which had a registered TD/CTD diagnosis. We then studied differentially exposed full siblings from 947 942 families; of these, 3563 families included siblings that were discordant for TD/CTD. Perinatal data were collected from the Medical Birth Register and TD/CTD diagnoses were collected from the National Patient Register, using a previously validated algorithm. In the fully adjusted models, impaired fetal growth, preterm birth, breech presentation and cesarean section were associated with a higher risk of TD/CTD, largely independent from shared family confounders and measured covariates. Maternal smoking during pregnancy was associated with risk of TD/CTD in a dose-response manner but the association was no longer statistically significant in the sibling comparison models or after the exclusion of comorbid attention-deficit/hyperactivity disorder. A dose-response relationship between the number of adverse perinatal events and increased risk for TD/CTD was also observed, with hazard ratios ranging from 1.41 (95% confidence interval (CI): 1.33-1.50) for one event to 2.42 (95% CI: 1.65-3.53) for five or more events. These results pave the way for future gene by environment interaction and epigenetic studies in TD/CTD.

A total-population multigenerational family clustering study of autoimmune diseases in obsessive-compulsive disorder and Tourette's/chronic tic disorders.

The association between obsessive-compulsive disorder (OCD) and Tourette's/chronic tic disorders (TD/CTD) with autoimmune diseases (ADs) is uncertain. In this nationwide study, we sought to clarify the patterns of comorbidity and familial clustering of a broad range of ADs in individuals with OCD, individuals with TD/CTD and their biological relatives. From a birth cohort of 7 465 455 individuals born in Sweden between 1940 and 2007, we identified 30 082 OCD and 7279 TD/CTD cases in the National Patient Register and followed them up to 31 December 2013. The risk of 40 ADs was evaluated in individuals with OCD, individuals with TD/CTD and their first- (siblings, mothers, fathers), second- (half siblings) and third-degree (cousins) relatives, compared with population controls. Individuals with OCD and TD/CTD had increased comorbidity with any AD (43% and 36%, respectively) and many individual ADs. The risk of any AD and several individual ADs was consistently higher among first-degree relatives than among second- and third-degree relatives of OCD and TD/CTD probands. The risk of ADs was very similar in mothers, fathers and siblings of OCD probands, whereas it tended to be higher in mothers and fathers of TD/CTD probands (compared with siblings). The results suggest a familial link between ADs in general (that is, not limited to Streptococcus-related conditions) and both OCD and TD/CTD. Additional mother-specific factors, such as the placental transmission of antibodies, cannot be fully ruled out, particularly in TD/CTD.

The sex-shift in single disease and multimorbid asthma and rhinitis during puberty - a study by MeDALL.

BACKGROUND: Cross-sectional studies suggested that allergy prevalence in childhood is higher in boys compared to girls, but it remains unclear whether this inequality changes after puberty. We examined the sex-specific prevalence of asthma and rhinitis as single and as multimorbid diseases before and after puberty onset in longitudinal cohort data. METHODS: In six European population-based birth cohorts of MeDALL, we assessed the outcomes: current rhinitis, current asthma, current allergic multimorbidity (ie, concurrent asthma and rhinitis), puberty status and allergic sensitization by specific serum antibodies (immunoglobulin E) against aero-allergens. With generalized estimating equations, we analysed the effects of sex, age, puberty (yes/no) and possible confounders on the prevalence of asthma and rhinitis, and allergic multimorbidity in each cohort separately and performed individual participant data meta-analysis. FINDINGS: We included data from 19 013 participants from birth to age 14-20 years. Current rhinitis only affected girls less often than boys before and after puberty onset: adjusted odds ratio for females vs males 0.79 (95%-confidence interval 0.73-0.86) and 0.86 (0.79-0.94), respectively (sex-puberty interaction P = .089). Similarly, for current asthma only, females were less often affected than boys both before and after puberty onset: 0.71, 0.63-0.81 and 0.81, 0.64-1.02, respectively (sex-puberty interaction P = .327). The prevalence of allergic multimorbidity showed the strongest sex effect before puberty onset (female-male-OR 0.55, 0.46-0.64) and a considerable shift towards a sex-balanced prevalence after puberty onset (0.89, 0.74-1.04); sex-puberty interaction: P < .001. INTERPRETATION: The male predominance in prevalence before puberty and the "sex-shift" towards females after puberty onset were strongest in multimorbid patients who had asthma and rhinitis concurrently.

Risk of eating disorders in immigrant populations.

OBJECTIVE: The risk of certain psychiatric disorders is elevated among immigrants. To date, no population studies on immigrant health have addressed eating disorders. We examined whether risk of eating disorders in first- and second-generation immigrants differs from native-born Danes and Swedes. METHOD: All individuals born 1984-2002 (Danish cohort) and 1989-1999 (Swedish cohort) and residing in the respective country on their 10th birthday were included. They were followed up for the development of eating disorders based on out-patient and in-patient data. RESULTS: The risks of all eating disorder types were lower among first-generation immigrants compared to the native populations: Incidence-rate ratio (95% confidence interval) was 0.39 (0.29, 0.51) for anorexia nervosa, 0.60 (0.42, 0.83) for bulimia nervosa, and 0.62 (0.47, 0.79) for other eating disorders in Denmark and 0.27 (0.21, 0.34) for anorexia nervosa, 0.30 (0.18, 0.51) for bulimia nervosa, and 0.39 (0.32, 0.47) for other eating disorders in Sweden. Likewise, second-generation immigrants by both parents were at lower risk, whereas those with only one foreign-born parent were not. CONCLUSION: The decreased risk of eating disorders among immigrants is opposite to what has been observed for other psychiatric disorders, particularly schizophrenia. Possible explanations include buffering sociocultural factors and underdetection in health care.

Physical and cognitive fitness in young adulthood and risk of amyotrophic lateral sclerosis at an early age.

BACKGROUND AND PURPOSE: There is a clinical impression that patients with amyotrophic lateral sclerosis (ALS) have a higher level of physical fitness and lower body mass index (BMI) than average. However, there is a lack of literature examining the relationship between cognitive fitness and ALS risk. In this study we explored the associations of both physical and cognitive fitness with future risk of ALS. METHODS: Data on physical fitness, BMI, intelligence quotient (IQ) and stress resilience were collected from 1 838 376 Swedish men aged 17-20 years at conscription during 1968-2010. Their subsequent ALS diagnoses were identified through the Swedish Patient Register. Hazard ratios (HRs) and 95% CIs from flexible parametric models were used to assess age-specific associations of physical fitness, BMI, IQ and stress resilience with ALS. RESULTS: We identified 439 incident ALS cases during follow-up (mean age at diagnosis: 48 years). Individuals with physical fitness above the highest tertile tended to have a higher risk of ALS before the age of 45 years (range of HRs: 1.42-1.75; statistically significant associations at age 41-43 years) compared with others. Individuals with BMI ≥ 25 tended to have a lower risk of ALS at all ages (range of HRs: 0.42-0.80; statistically significant associations at age 42-48 years) compared with those with BMI < 25. Individuals with IQ above the highest tertile had a statistically significantly increased risk of ALS at an age of 56 years and above (range of HRs: 1.33-1.81), whereas individuals with stress resilience above the highest tertile had a lower risk of ALS at an age of 55 years and below (range of HRs: 0.47-0.73). CONCLUSIONS: Physical fitness, BMI, IQ and stress resilience in young adulthood might be associated with the development of ALS at an early age.

Paternal age at childbirth and eating disorders in offspring.

BACKGROUND: Advanced paternal age at childbirth is associated with psychiatric disorders in offspring, including schizophrenia, bipolar disorder and autism. However, few studies have investigated paternal age's relationship with eating disorders in offspring. In a large, population-based cohort, we examined the association between paternal age and offspring eating disorders, and whether that association remains after adjustment for potential confounders (e.g. parental education level) that may be related to late/early selection into fatherhood and to eating disorder incidence. METHOD: Data for 2 276 809 individuals born in Sweden 1979-2001 were extracted from Swedish population and healthcare registers. The authors used Cox proportional hazards models to examine the effect of paternal age on the first incidence of healthcare-recorded anorexia nervosa (AN) and all eating disorders (AED) occurring 1987-2009. Models were adjusted for sex, birth order, maternal age at childbirth, and maternal and paternal covariates including country of birth, highest education level, and lifetime psychiatric and criminal history. RESULTS: Even after adjustment for covariates including maternal age, advanced paternal age was associated with increased risk, and younger paternal age with decreased risk, of AN and AED. For example, the fully adjusted hazard ratio for the 45+ years (v. the 25-29 years) paternal age category was 1.32 [95% confidence interval (CI) 1.14-1.53] for AN and 1.26 (95% CI 1.13-1.40) for AED. CONCLUSIONS: In this large, population-based cohort, paternal age at childbirth was positively associated with eating disorders in offspring, even after adjustment for potential confounders. Future research should further explore potential explanations for the association, including de novo mutations in the paternal germline.

Mental illness and suicide after self-harm among young adults: long-term follow-up of self-harm patients, admitted to hospital care, in a national cohort.

BACKGROUND: Self-harm among young adults is a common and increasing phenomenon in many parts of the world. The long-term prognosis after self-harm at young age is inadequately known. We aimed to estimate the risk of mental illness and suicide in adult life after self-harm in young adulthood and to identify prognostic factors for adverse outcome. METHOD: We conducted a national population-based matched case-cohort study. Patients aged 18-24 years (n = 13 731) hospitalized after self-harm between 1990 and 2003 and unexposed individuals of the same age (n = 137 310 ) were followed until December 2009. Outcomes were suicide, psychiatric hospitalization and psychotropic medication in short-term (1-5 years) and long-term (>5 years) follow-up. RESULTS: Self-harm implied an increased relative risk of suicide during follow-up [hazard ratio (HR) 16.4, 95% confidence interval (CI) 12.9-20.9). At long-term follow-up, 20.3% had psychiatric hospitalizations and 51.1% psychotropic medications, most commonly antidepressants and anxiolytics. There was a six-fold risk of psychiatric hospitalization (HR 6.3, 95% CI 5.8-6.8) and almost three-fold risk of psychotropic medication (HR 2.8, 95% CI 2.7-3.0) in long-term follow-up. Mental disorder at baseline, especially a psychotic disorder, and a family history of suicide were associated with adverse outcome among self-harm patients. CONCLUSION: We found highly increased risks of future mental illness and suicide among young adults after self-harm. A history of a mental disorder was an important indicator of long-term adverse outcome. Clinicians should consider the substantially increased risk of suicide among self-harm patients with psychotic disorders.

Depression or anxiety in adult twins is associated with asthma diagnosis but not with offspring asthma.

BACKGROUND: Asthma is common in both children and adults in the Western world, just like anxiety and depression. While some research has revealed that these diseases might share important environmental and pathophysiological aspects, the exact mechanisms still remain unclear. OBJECTIVE: To study the correlation firstly between depression or anxiety and asthma diagnosis in adult twins and secondly the association between parental depression or anxiety and offspring asthma in children of twins. METHODS: In total, 24 685 adult twins aged 20-47 years were interviewed or completed a Web-based questionnaire and their children were identified through the Multi-Generation Register. Asthma diagnosis was obtained from the Patient Register and the Prescribed Drug Register. Assessment of depression and anxiety was obtained from questionnaires using Center for Epidemiologic Studies Depression Scale (CES-D), major depression and generalized anxiety disorder (GAD) from DSM-IV. The association between depression or anxiety and asthma was analyzed with logistic regression adjusting for confounders in twins and offspring. To address genetic and familial environmental confounding, we performed a cotwin analysis using disease-discordant twin pairs. RESULTS: We found an association between asthma and CES-D, major depression and GAD, for example adjusted OR for major depression and register-based asthma 1.56 (1.36-1.79). Most of the point estimates remained in the co-twin control analysis, indicating that the association was likely not due to genetic or familial environmental factors. There was no association between parental depression and/or anxiety and asthma diagnosis in the offspring which implies lack of genetic confounding. CONCLUSIONS: We found an association between own asthma diagnosis and anxiety or depression, but not with offspring asthma. Our results indicate that the associations were not due to confounding from genes or environment shared by the twins.

Heritability and confirmation of genetic association studies for childhood asthma in twins.

BACKGROUND: Although the genetics of asthma has been extensively studied using both quantitative and molecular genetic analysis methods, both approaches lack studies specific to the childhood phenotype and including other allergic diseases. This study aimed to give specific estimates for the heritability of childhood asthma and other allergic diseases, to attempt to replicate findings from genomewide association studies (GWAS) for childhood asthma and to test the same variants against other allergic diseases. METHODS: In a cohort of 25 306 Swedish twins aged 9 or 12 years, data on asthma were available from parental interviews and population-based registers. The interviews also inquired about wheeze, hay fever, eczema, and food allergy. Through structural equation modeling, the heritability of all phenotypes was calculated. A subset of 10 075 twins was genotyped for 16 single nucleotide polymorphisms (SNPs) selected from previous GWAS; these were first tested for association with asthma and significant findings also against the other allergic diseases. RESULTS: The heritability of any childhood asthma was 0.82 (95% CI 0.79-0.85). For the other allergic diseases, the range was approximately 0.60-0.80. Associations for six SNPs with asthma were replicated, including rs2305480 in the GSDMB gene (OR 0.80, 95% CI 0.74-0.86, P = 1.5*10(-8) ; other significant associations all below P = 3.5*10(-4) ). Of these, only rs3771180 in IL1RL1 was associated with any other allergic disease (for hay fever, OR 0.64, 95% CI 0.53-0.77, P = 2.5*10(-6) ). CONCLUSION: Asthma and allergic diseases of childhood are highly heritable, and these high-risk genetic variants associated specifically with childhood asthma, except for one SNP shared with hay fever.

The association between childhood relocations and subsequent risk of suicide attempt, psychiatric problems, and low academic achievement.

BACKGROUND: Given the frequency with which families change residences, the effects of childhood relocations have gained increasing research attention. Many researchers have demonstrated that childhood relocations are associated with a variety of adverse outcomes. However, drawing strong causal claims remains problematic due to uncontrolled confounding factors. METHOD: We utilized longitudinal, population-based Swedish registers to generate a nationally representative sample of offspring born 1983-1997 (n = 1 510 463). Using Cox regression and logistic regression, we examined the risk for numerous adverse outcomes after childhood relocation while controlling for measured covariates. To account for unmeasured genetic and environmental confounds, we also compared differentially exposed cousins and siblings. RESULTS: In the cohort baseline model, each annual relocation was associated with risk for the adverse outcomes, including suicide attempt [hazard ratio (HR) 1.19, 95% confidence interval (CI) 1.19-1.20]. However, when accounting for offspring and parental covariates (HR 1.08, 95% CI 1.07-1.09), as well as genetic and environmental confounds shared by cousins (HR 1.07, 95% CI 1.05-1.09) and siblings (HR 1.00, 95% CI 0.97-1.04), the risk for suicide attempt attenuated. We found a commensurate pattern of results for severe mental illness, substance abuse, criminal convictions, and low academic achievement. CONCLUSIONS: Previous research may have overemphasized the independent association between relocations and later adverse outcomes. The results suggest that the association between childhood relocations and suicide attempt, psychiatric problems, and low academic achievement is partially explained by genetic and environmental confounds correlated with relocations. This study demonstrates the importance of using family-based, quasi-experimental designs to test plausible alternate hypotheses when examining causality.