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1.  A genome-wide association study of anorexia nervosa 
Boraska, Vesna | Franklin, Christopher S | Floyd, James AB | Thornton, Laura M | Huckins, Laura M | Southam, Lorraine | Rayner, N William | Tachmazidou, Ioanna | Klump, Kelly L | Treasure, Janet | Lewis, Cathryn M | Schmidt, Ulrike | Tozzi, Federica | Kiezebrink, Kirsty | Hebebrand, Johannes | Gorwood, Philip | Adan, Roger AH | Kas, Martien JH | Favaro, Angela | Santonastaso, Paolo | Fernández-Aranda, Fernando | Gratacos, Monica | Rybakowski, Filip | Dmitrzak-Weglarz, Monika | Kaprio, Jaakko | Keski-Rahkonen, Anna | Raevuori, Anu | Van Furth, Eric F | Landt, Margarita CT Slof-Op t | Hudson, James I | Reichborn-Kjennerud, Ted | Knudsen, Gun Peggy S | Monteleone, Palmiero | Kaplan, Allan S | Karwautz, Andreas | Hakonarson, Hakon | Berrettini, Wade H | Guo, Yiran | Li, Dong | Schork, Nicholas J. | Komaki, Gen | Ando, Tetsuya | Inoko, Hidetoshi | Esko, Tõnu | Fischer, Krista | Männik, Katrin | Metspalu, Andres | Baker, Jessica H | Cone, Roger D | Dackor, Jennifer | DeSocio, Janiece E | Hilliard, Christopher E | O'Toole, Julie K | Pantel, Jacques | Szatkiewicz, Jin P | Taico, Chrysecolla | Zerwas, Stephanie | Trace, Sara E | Davis, Oliver SP | Helder, Sietske | Bühren, Katharina | Burghardt, Roland | de Zwaan, Martina | Egberts, Karin | Ehrlich, Stefan | Herpertz-Dahlmann, Beate | Herzog, Wolfgang | Imgart, Hartmut | Scherag, André | Scherag, Susann | Zipfel, Stephan | Boni, Claudette | Ramoz, Nicolas | Versini, Audrey | Brandys, Marek K | Danner, Unna N | de Kovel, Carolien | Hendriks, Judith | Koeleman, Bobby PC | Ophoff, Roel A | Strengman, Eric | van Elburg, Annemarie A | Bruson, Alice | Clementi, Maurizio | Degortes, Daniela | Forzan, Monica | Tenconi, Elena | Docampo, Elisa | Escaramís, Geòrgia | Jiménez-Murcia, Susana | Lissowska, Jolanta | Rajewski, Andrzej | Szeszenia-Dabrowska, Neonila | Slopien, Agnieszka | Hauser, Joanna | Karhunen, Leila | Meulenbelt, Ingrid | Slagboom, P Eline | Tortorella, Alfonso | Maj, Mario | Dedoussis, George | Dikeos, Dimitris | Gonidakis, Fragiskos | Tziouvas, Konstantinos | Tsitsika, Artemis | Papezova, Hana | Slachtova, Lenka | Martaskova, Debora | Kennedy, James L. | Levitan, Robert D. | Yilmaz, Zeynep | Huemer, Julia | Koubek, Doris | Merl, Elisabeth | Wagner, Gudrun | Lichtenstein, Paul | Breen, Gerome | Cohen-Woods, Sarah | Farmer, Anne | McGuffin, Peter | Cichon, Sven | Giegling, Ina | Herms, Stefan | Rujescu, Dan | Schreiber, Stefan | Wichmann, H-Erich | Dina, Christian | Sladek, Rob | Gambaro, Giovanni | Soranzo, Nicole | Julia, Antonio | Marsal, Sara | Rabionet, Raquel | Gaborieau, Valerie | Dick, Danielle M | Palotie, Aarno | Ripatti, Samuli | Widén, Elisabeth | Andreassen, Ole A | Espeseth, Thomas | Lundervold, Astri | Reinvang, Ivar | Steen, Vidar M | Le Hellard, Stephanie | Mattingsdal, Morten | Ntalla, Ioanna | Bencko, Vladimir | Foretova, Lenka | Janout, Vladimir | Navratilova, Marie | Gallinger, Steven | Pinto, Dalila | Scherer, Stephen | Aschauer, Harald | Carlberg, Laura | Schosser, Alexandra | Alfredsson, Lars | Ding, Bo | Klareskog, Lars | Padyukov, Leonid | Finan, Chris | Kalsi, Gursharan | Roberts, Marion | Logan, Darren W | Peltonen, Leena | Ritchie, Graham RS | Barrett, Jeffrey C | Estivill, Xavier | Hinney, Anke | Sullivan, Patrick F | Collier, David A | Zeggini, Eleftheria | Bulik, Cynthia M
Molecular psychiatry  2014;19(10):1085-1094.
Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2,907 cases with AN from 14 countries (15 sites) and 14,860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery datasets. Seventy-six (72 independent) SNPs were taken forward for in silico (two datasets) or de novo (13 datasets) replication genotyping in 2,677 independent AN cases and 8,629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication datasets comprised 5,551 AN cases and 21,080 controls. AN subtype analyses (1,606 AN restricting; 1,445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01×10-7) in SOX2OT and rs17030795 (P=5.84×10-6) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76×10-6) between CUL3 and FAM124B and rs1886797 (P=8.05×10-6) near SPATA13. Comparing discovery to replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4×10-6), strongly suggesting that true findings exist but that our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field.
doi:10.1038/mp.2013.187
PMCID: PMC4325090  PMID: 24514567
anorexia nervosa; eating disorders; GWAS; genome-wide association study; body mass index; metabolic
2.  Parental Knowledge is an Environmental Influence on Adolescent Externalizing 
Background
There is evidence both that parental monitoring is an environmental influence serving to diminish adolescent externalizing problems and that this association may be driven by adolescents’ characteristics via genetic and/or environmental mechanisms, such that adolescents with fewer problems tell their parents more, and therefore appear to be better monitored. Without information on how parents’ and children’s genes and environments influence correlated parent and child behaviors, it is impossible to clarify the mechanisms underlying this association.
Method
The present study used the Extended Children of Twins model to distinguish types of gene-environment correlation and direct environmental effects underlying associations between parental knowledge and adolescent (age 11-22 years) externalizing behavior with a Swedish sample of 909 twin parents and their adolescent offspring and a US-based sample of 405 White adolescent siblings and their parents.
Results
Results suggest that more parental knowledge is associated with less adolescent externalizing via a direct environmental influence independent of any genetic influences. There was no evidence of a child-driven explanation of the association between parental knowledge and adolescent externalizing problems.
Conclusions
In this sample of adolescents, parental knowledge exerted an environmental influence on adolescent externalizing after accounting for genetic influences of parents and adolescents. Because the association between parenting and child development originates in the parent, treatment for adolescent externalizing must not only include parents but should focus on altering their parental style. Thus, findings suggest that teaching parents better knowledge-related monitoring strategies is likely to help reduce externalizing problems in adolescents.
doi:10.1111/jcpp.12288
PMCID: PMC4280345  PMID: 24975929
Gene-Environment Correlation; Adolescent Externalizing; Parental Monitoring; Parental Knowledge; Extended Children of Twins
3.  Binge eating and menstrual dysfunction 
Objective
The relation between eating disorders and menstrual function has been widely studied, but it is unknown whether the behavior of binge eating itself is related to menstrual dysfunction.
Methods
The 11,503 women included in this study were from the Swedish Twin study of Adults: Genes and Environment. The associations between menstrual dysfunction and binge eating were analyzed using logistic regression or multiple linear regression models with generalized estimation equations.
Results
Women who reported lifetime binge eating were more likely to report either amenorrhea or oligomenorrhea than women who reported no binge eating. These results persisted when controlling for compensatory behaviors including self-induced vomiting, laxative use, and diuretic use. No differences between women with and without a history of binge eating were observed for age at menarche.
Conclusion
Even when controlling for the effect of compensatory behaviors, the behavior of binge eating is associated with menstrual dysfunction. Metabolic and endocrinological factors could underlie this association. Careful evaluation of menstrual status is warranted for women with all eating disorders, not just anorexia nervosa.
doi:10.1016/j.jpsychores.2013.11.011
PMCID: PMC3909535  PMID: 24360136
menstruation; amenorrhea; oligomenorrhea; binge eating; binge eating disorder
4.  Offspring psychopathology following preconception, prenatal, and postnatal maternal bereavement stress 
Psychological medicine  2013;44(1):10.1017/S0033291713000780.
Background
Preconception, prenatal, and postnatal maternal stress are associated with increased offspring psychopathology, but findings are inconsistent and need replication. We estimated associations between maternal bereavement stress and offspring autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), bipolar disorder, schizophrenia, suicide attempt, and completed suicide.
Methods
Using Swedish registers, we conducted the largest population-based study to date examining associations between stress exposure in 738,144 offspring born 1992–2000 for childhood outcomes and 2,155,221 offspring born 1973–1997 for adult outcomes with follow-up through 2009. Maternal stress was defined as death of a first degree relative during 6 months before conception, across pregnancy, or the first two postnatal years. Cox proportional survival analyses were used to obtain hazard ratios (HR) in unadjusted and adjusted analyses.
Results
Marginal increased risk of bipolar disorder and schizophrenia following preconception bereavement stress was not significant. Third trimester prenatal stress increased risk of ASD (adjusted HR=1.58, 95% CI: 1.15–2.17) and ADHD (adjusted HR=1.31, 95% CI: 1.04–1.66). First postnatal year stress increased risk for offspring suicide attempt (adjusted HR=1.13, 95% CI: 1.02–1.25) and completed suicide (adjusted HR=1.51, 95% CI: 1.08–2.11). Bereavement stress during the second postnatal year increased risk of ASD (adjusted HR=1.30, 95% CI: 1.09–1.55).
Conclusions
Further research is needed on associations between preconception stress and psychopathological outcomes. Prenatal bereavement stress increases risk of offspring ASD and ADHD. Postnatal bereavement stress moderately increases risk of offspring suicide attempt, completed suicide, and ASD. Smaller previous studies may have overestimated associations between early stress and psychopathological outcomes.
doi:10.1017/S0033291713000780
PMCID: PMC3766407  PMID: 23591021
stress; preconception; prenatal; postnatal; psychiatric; psychopathology; autism; attention-deficit/hyperactivity disorder; schizophrenia; suicide
5.  Familial Confounding of the Association between Maternal Smoking During Pregnancy and ADHD in Offspring 
Background
Maternal Smoking During Pregnancy (SDP) has consistently been associated with increased risk of attention deficit hyperactivity disorder (ADHD) in offspring, but recent studies indicate that this association might be due to unmeasured familial confounding.
Methods
A total of 813 030 individuals born in Sweden between 1992 and 2000 were included in this nationwide population based cohort study. Data on maternal SDP and ADHD diagnosis were obtained from national registers and patients were followed up from the age of 3 to the end of 2009. Hazard Ratios (HRs) were estimated using stratified Cox regression models. Cousin and sibling data were used to control for unmeasured familial confounding.
Results
At the population level maternal SDP predicted ADHD in offspring (HRModerateSDP=1.89; HRHighSDP=2.50). This estimate gradually attenuated towards the null when adjusting for measured confounders (HRModerateSDP=1.62; HRHighSDP=2.04), unmeasured confounders shared within the extended family (i.e., cousin comparison) (HRModerateSDP= 1.45; HRHighSDP=1.69), and unmeasured confounders within the nuclear family (i.e., sibling comparison) (HRModerateSDP=0.88; HRHighSDP=0.84).
Conclusions
Our results suggest that the association between maternal SDP and offspring ADHD are due to unmeasured familial confounding.
doi:10.1111/jcpp.12124
PMCID: PMC4217138  PMID: 25359172
Maternal smoking during pregnancy; attention-deficit/hyperactivity disorder; confounding; sibling comparisons
6.  Thinking positively: The genetics of high intelligence 
Intelligence  2015;48:123-132.
High intelligence (general cognitive ability) is fundamental to the human capital that drives societies in the information age. Understanding the origins of this intellectual capital is important for government policy, for neuroscience, and for genetics. For genetics, a key question is whether the genetic causes of high intelligence are qualitatively or quantitatively different from the normal distribution of intelligence. We report results from a sibling and twin study of high intelligence and its links with the normal distribution. We identified 360,000 sibling pairs and 9000 twin pairs from 3 million 18-year-old males with cognitive assessments administered as part of conscription to military service in Sweden between 1968 and 2010. We found that high intelligence is familial, heritable, and caused by the same genetic and environmental factors responsible for the normal distribution of intelligence. High intelligence is a good candidate for “positive genetics” — going beyond the negative effects of DNA sequence variation on disease and disorders to consider the positive end of the distribution of genetic effects.
Highlights
•High intelligence is as familial and heritable as the rest of the distribution.•There are no substantial genetic effects unique to high intelligence.•There are no substantial environmental effects unique to high intelligence.•Studying the “positive” end of trait dimensions is rare, and potentially very useful.
doi:10.1016/j.intell.2014.11.005
PMCID: PMC4286575  PMID: 25593376
Intelligence; Human genetics; Twins; Siblings; Positive genetics
7.  Association study between autistic-like traits and polymorphisms in the autism candidate regions RELN, CNTNAP2, SHANK3, and CDH9/10 
Molecular Autism  2014;5(1):55.
Background
Autistic-like traits (ALTs) are continuously distributed in the general population, with the autism spectrum disorder (ASD) at the upper extreme end. A genetic overlap has been shown between ALTs and ASD, indicating that common variation in ASD candidate genes may also influence ALTs. In our study, we have investigated the SNP rs4307059 that has been associated with both ALTs and ASD. In addition, we genotyped polymorphisms in a selection of genes involved in synaptic functioning, that is, SHANK3, RELN, and CNTNAP2, which repeatedly have been associated with ASD. The possible associations of these polymorphisms with ALTs, as well as genetic factors for neurodevelopmental problems (NDPs), were investigated in a large cohort from the general population: The Child and Adolescent Twin Study in Sweden. For analyses of ALTs and NDPs, 12,319 subjects (including 2,268 monozygotic (MZ) and 3,805 dizygotic (DZ) twin pairs) and 8,671 subjects (including 2,243 MZ and 2,044 DZ twin pairs), respectively, were included in the analyses.
Findings
We could not replicate the previous association between rs4307059 and social communication impairment. Moreover, common variations in CNTNAP2 (rs7794745 and rs2710102), RELN (rs362691), and SHANK3 (rs9616915) were not significantly associated with ALTs in our study.
Conclusions
Our results do not suggest that the investigated genes, which previously has been found associated with ASD diagnosis, have any major influence on ALTs in children from the general population.
Electronic supplementary material
The online version of this article (doi:10.1186/2040-2392-5-55) contains supplementary material, which is available to authorized users.
doi:10.1186/2040-2392-5-55
PMCID: PMC4276093  PMID: 25540679
Autistic-like traits; Autism spectrum disorder; CNTNAP2; RELN; rs4307059; SHANK3; A-TAC; CATSS
8.  Familial Aggregation of Schizophrenia: The Moderating Effect of Age at Onset, Parental Immigration, Paternal Age and Season of Birth 
Aim
An abundance of evidence has firmly established the familial aggregation of schizophrenia. The aim of this study was to examine how age at onset, parental characteristics and season of birth modify the familiality in schizophrenia.
Methods
A population-based cohort was created by linking the Swedish Multi-Generation and Hospital Discharge Registers. Among 5 075 998 full siblings born between 1932 through 1990, 16 346 cases of schizophrenia were identified. Familial aggregation was measured by the sibling recurrence-risk ratio, defined as the risk of schizophrenia among full siblings of schizophrenia patients compared with the risk among siblings of unaffected subjects.
Results
We found a statistically significantly lower recurrence-risk ratio in siblings of later onset cases (7.2; 95%CI 6.7-7.9) than of early onset cases (10.8; 95%CI 9.4-12.2). A lower recurrence-risk ratio was observed among offspring to fathers above 40 years (6.3; 95%CI 5.3-7.3) as compared with offspring of younger fathers (8.6; 95%CI 8.0-9.3). Further, among offspring to parents born outside Sweden the recurrence-risk ratio was statistically significantly lower (maternal immigrants 4.8; 95%CI 4.0-5.7, paternal immigrants 5.7; 95%CI 4.6-6.9) than among offspring to parents born in Sweden.
Conclusions
The familial aggregation of schizophrenia was reduced by higher age at onset, advancing paternal age and immigrant status of parents.
doi:10.1177/1403494811420485
PMCID: PMC4229243  PMID: 21930618
schizophrenia; familial aggregation; recurrence-risk ratio; age at onset; paternal age; migration
9.  Suicide, Hospital-Presenting Suicide Attempts, and Criminality in Bipolar Disorder: Examination of Risk for Multiple Adverse Outcomes 
The Journal of clinical psychiatry  2014;75(8):e809-e816.
Objective
To compare risks for suicidality and criminality in a national cohort of people diagnosed with bipolar disorder, and to assess how risk factor profiles differ between these outcomes.
Method
We conducted 2 case-cohort studies using interlinked Swedish national registers. Primarily, using International Classification of Diseases (ICD) coding, we identified 15,337 people diagnosed with bipolar disorder, 1973–2009, matched by age and gender to 20 individuals per case sampled randomly from the general population. We estimated risks of suicide and hospital-presenting attempted suicide, and violent and nonviolent criminal offending. We separately assessed these risks among 14,677 unaffected siblings matched to a second general population sample.
Results
22.2% of bipolar disorder cohort members engaged in suicidal or criminal acts after diagnosis. They were at greatly elevated risk for completed suicide (risk ratio = 18.8; 95% CI, 16.0–22.2), attempted suicide (risk ratio = 14.3; 95% CI, 13.5–15.2), violent crime (risk ratio = 5.0; 95% CI, 4.6–5.4), and nonviolent crime (risk ratio = 2.9; 95% CI, 2.8–3.1) compared with the general population. Elevations in risk were far less marked among the unaffected siblings than in the bipolar disorder cohort. Three factors independently predicted raised risk of all 4 adverse outcomes: if the first 2 patient episodes for bipolar disorder required admission, a history of attempted suicide, and a history of diagnosed alcohol/drug disorder. Criminal offending before bipolar diagnosis was an especially strong independent predictor of criminality after diagnosis.
Conclusions
The combined risk of suicidality or criminality is substantially elevated in both relative and absolute terms. Clinical prediction rules focusing on multiple vulnerabilities following onset of bipolar disorder, especially when there is history of attempted suicide, substance misuse disorders, or criminal offending, may improve risk management.
doi:10.4088/JCP.13m08899
PMCID: PMC4226039  PMID: 25191918
10.  Binge Eating, Body Mass Index, and Gastrointestinal Symptoms 
Journal of psychosomatic research  2013;75(5):10.1016/j.jpsychores.2013.08.009.
Objective
Symptoms of both gastroesophageal reflux disease (GERD) and irritable bowel syndrome (IBS) are frequently reported by individuals who binge eat. Higher body mass index (BMI) has also been associated with these disorders and with binge eating (BE). However, it is unknown whether BE influences GERD/IBS and how BMI might affect these associations. Thus, we examined the potential associations among BE, GERD, IBS, and BMI.
Methods
Participants were from the Swedish Twin study of Adults: Genes and Environment (STAGE) and provided information on disordered eating behavior, BMI, gastrointestinal (GI) disorders, and commonly comorbid psychiatric and somatic illnesses. Key features of GERD and IBS were identified to create modified definitions of both disorders that were used as primary outcome variables. Logistic regression models were applied to determine the association between BE and each GERD/IBS both independently and in the context of BMI and other commonly comorbid psychiatric and somatic morbidities.
Results
Prevalence estimates for GERD and IBS were higher among women than men (all p-values < .001). Only the association between BE and IBS was significant in both men and women after adjustment for BMI and the psychiatric/somatic morbidities.
Conclusion
BE appears to be an important consideration in the presence of IBS symptoms in both men and women, even when considering the impact of BMI and other commonly comorbid conditions. This association underscores the importance of routine assessment of BE in patients presenting with IBS to effectively manage the concurrent presentation of these problems.
doi:10.1016/j.jpsychores.2013.08.009
PMCID: PMC3817501  PMID: 24182635
Binge eating; body mass index; gastroesophageal reflux disease; irritable bowel syndrome
11.  Preterm birth and mortality and morbidity: A population-based quasi-experimental study 
JAMA psychiatry (Chicago, Ill.)  2013;70(11):10.1001/jamapsychiatry.2013.2107.
Context
Preterm birth is associated with increased mortality and morbidity. However, previous studies have been unable to rigorously examine whether confounding factors cause these associations rather than the harmful effects of being born preterm.
Objective
To estimate the extent to which the associations between early gestational age and offspring mortality and morbidity were due to confounds by using a quasi-experimental design, the sibling-comparison approach, and controlling for statistical covariates that varied within families.
Design, Setting, and Participants
A population-based cohort study, combining Swedish registries to identify all individuals born in Sweden from 1973–2008 (n=3,300,708 offspring of 1,736,735 mothers) and link them with multiple outcomes.
Main Outcome Measures
Offspring mortality (during infancy and throughout young adulthood) and psychiatric (psychotic or bipolar disorder, autism, ADHD, suicide attempts, substance use, and criminality), academic (failing grades and educational attainment), and social (partnering, parenthood, low income, social welfare benefits) outcomes through 2009.
Results
In the population, there was a dose-response relation between early gestation and the outcome measures. For instance, extreme preterm birth (23–27 weeks of gestation) was associated with infant mortality (OR=288.1, 95% CI=271.7–305.5), autism (HR=3.2, CI=2.6–4.0), low educational attainment (HR=1.7, CI=1.5–2.0), and social welfare benefits (HR=1.3, CI=1.2–1.5) compared to offspring born at term. The associations between early gestation and mortality and psychiatric morbidity generally were robust when comparing differentially exposed siblings and controlling for statistical covariates, whereas the associations with academic and some social problems were greatly or completely attenuated in the fixed effects models.
Conclusions
The mechanisms responsible for the associations between preterm birth and mortality and morbidity are outcome-specific. Associations between preterm birth and mortality and psychiatric morbidity were largely independent of shared familial confounds and measured covariates, consistent with a causal inference. Some associations, particularly predicting suicide attempt, educational attainment, and social welfare benefits were due to confounding factors, however.
doi:10.1001/jamapsychiatry.2013.2107
PMCID: PMC3823714  PMID: 24068297
12.  FAMILY HISTORY OF SCHIZOPHRENIA AND BIPOLAR DISORDER AS RISK FACTORS FOR AUTISM 
Archives of general psychiatry  2012;69(11):1099-1103.
Background
The clinical and etiological relation between autism spectrum disorders (ASD) and schizophrenia is unclear. The degree to which these disorders share a basis in etiology has important implications for clinicians, researchers, and those affected. Our objective was to determine if a family history of schizophrenia and/or bipolar disorder was a risk factor for ASD. We conducted a case-control evaluation of histories of schizophrenia or bipolar disorder in first-degree relatives of probands in three samples, population registers in Sweden, Stockholm County, and Israel. Probands met criteria for ASD, and affection status of parents and siblings for schizophrenia and bipolar disorder were established.
Findings
The presence of schizophrenia in parents was associated with an increased risk for ASD in a Swedish national cohort (odds ratio 2.9, 95% CI 2.5–3.4) and in a Stockholm County cohort (odds ratio 2.9, 95% CI 2.0–4.1). Similarly, schizophrenia in a sibling was associated with an increased risk for ASD in a Swedish national cohort (odds ratio 2.6, 95% CI 2.0–3.2) and in an Israeli conscription cohort (odds ratio 12.1, 95% CI 4.5–32). Bipolar disorder showed a similar pattern of associations but of lesser magnitude.
Interpretation
Findings from these three registers along with consistent findings from a similar study in Denmark suggest that ASD, schizophrenia, and bipolar disorder share common etiological factors.
Funding
Swedish Council for Working Life and Social Research, the Swedish Research Council, and the Beatrice and Samuel A. Seaver Foundation.
doi:10.1001/archgenpsychiatry.2012.730
PMCID: PMC4187103  PMID: 22752149
autism spectrum disorder; schizophrenia; bipolar disorder; family history; genetics; risk factor; exposure; genetic epidemiology
13.  The Critical Need for Family-Based, Quasi-Experimental Designs in Integrating Genetic and Social Science Research 
American journal of public health  2013;103(0 1):S46-S55.
Researchers have identified environmental risks that predict subsequent psychological and medical problems. Based on these correlational findings, researchers have developed and tested complex developmental models and have examined biological moderating factors (e.g., gene-environment interactions). In this context, we stress the critical need for researchers to use family-based, quasi-experimental designs when trying to integrate genetic and social science research involving environmental variables because these designs rigorously examine causal inferences by rigorously testing competing hypotheses. We argue that sibling-comparison, offspring of twins/siblings, in vitro fertilization designs, and other genetically-informed approaches play a unique role in bridging gaps between basic biological and social science research. We exemplify these principles using studies on maternal smoking during pregnancy.
doi:10.2105/AJPH.2013.301252
PMCID: PMC3778076  PMID: 23927516
14.  Antipsychotics, mood stabilisers, and risk of violent crime 
Lancet  2014;384(9949):1206-1214.
Summary
Background
Antipsychotics and mood stabilisers are prescribed widely to patients with psychiatric disorders worldwide. Despite clear evidence for their efficacy in relapse prevention and symptom relief, their effect on some adverse outcomes, including the perpetration of violent crime, is unclear. We aimed to establish the effect of antipsychotics and mood stabilisers on the rate of violent crime committed by patients with psychiatric disorders in Sweden.
Methods
We used linked Swedish national registers to study 82 647 patients who were prescribed antipsychotics or mood stabilisers, their psychiatric diagnoses, and subsequent criminal convictions in 2006–09. We did within-individual analyses to compare the rate of violent criminality during the time that patients were prescribed these medications versus the rate for the same patients while they were not receiving the drugs to adjust for all confounders that remained constant within each participant during follow-up. The primary outcome was the occurrence of violent crime, according to Sweden’s national crime register.
Findings
In 2006–09, 40 937 men in Sweden were prescribed antipsychotics or mood stabilisers, of whom 2657 (6·5%) were convicted of a violent crime during the study period. In the same period, 41 710 women were prescribed these drugs, of whom 604 (1·4 %) had convictions for violent crime. Compared with periods when participants were not on medication, violent crime fell by 45% in patients receiving antipsychotics (hazard ratio [HR] 0·55, 95% CI 0·47–0·64) and by 24% in patients prescribed mood stabilisers (0·76, 0·62–0·93). However, we identified potentially important differences by diagnosis—mood stabilisers were associated with a reduced rate of violent crime only in patients with bipolar disorder. The rate of violence reduction for antipsychotics remained between 22% and 29% in sensitivity analyses that used different outcomes (any crime, drug-related crime, less severe crime, and violent arrest), and was stronger in patients who were prescribed higher drug doses than in those prescribed low doses. Notable reductions in violent crime were also recorded for depot medication (HR adjusted for concomitant oral medications 0·60, 95% CI 0·39–0·92).
Interpretation
In addition to relapse prevention and psychiatric symptom relief, the benefits of antipsychotics and mood stabilisers might also include reductions in the rates of violent crime. The potential effects of these drugs on violence and crime should be taken into account when treatment options for patients with psychiatric disorders are being considered.
Funding
The Wellcome Trust, the Swedish Prison and Probation Service, the Swedish Research Council, and the Swedish Research Council for Health, Working Life and Welfare.
doi:10.1016/S0140-6736(14)60379-2
PMCID: PMC4165625  PMID: 24816046
15.  Teenage childbirth and young adult criminal convictions: A quasi-experimental study of criminal outcomes for teenage mothers 
Journal of criminal justice  2013;41(5):318-323.
Purpose
Teenage childbirth is associated with poor psychosocial outcomes for teen mothers. One example is that teen mothers have higher rates of antisocial behavior. The extant research has not been able to determine if teenage motherhood is independently associated with criminal behavior, or if the association is due to selection factors associated with both teenage childbirth and criminal behavior.
Methods
We used longitudinal data from Swedish national registers and sibling-comparisons (both full- and half-siblings) to identify the extent to which there is an independent association between teenage childbirth and mothers’ likelihood of criminal conviction between ages 20-30, or if the association is confounded by familial (including genetic or environmental) factors that make sisters similar.
Results
Women who began childbearing as teenagers were more likely to be convicted of a crime in young adulthood compared to women who delayed childbearing. When sisters were compared, the association between teenage childbirth and criminal convictions disappeared. Multivariate behavior genetic analyses suggest genetic and shared environmental account for the association.
Conclusions
The statistical association between teenage childbirth and early adulthood criminal convictions is confounded by genetic and shared environmental factors that influence both the likelihood of teenage childbirth and risk of early adulthood criminal conviction.
PMCID: PMC3769799  PMID: 24039311
Teenage mothers; teenage childbirth; criminality
16.  A behavioral-genetic investigation of bulimia nervosa and its relationship with alcohol use disorder 
Psychiatry research  2013;208(3):232-237.
Bulimia nervosa (BN) and alcohol use disorder (AUD) frequently co-occur and may share genetic factors; however, the nature of their association is not fully understood. We assessed the extent to which the same genetic and environmental factors contribute to liability to BN and AUD. A bivariate structural equation model using a Cholesky decomposition was fit to data from 7,241 women who participated in the Swedish Twin study of Adults: Genes and Environment. The proportion of variance accounted for by genetic and environmental factors for BN and AUD and the genetic and environmental correlations between these disorders were estimated. In the best-fitting model, the heritability estimates were 0.55 (95% CI: 0.37; 0.70) for BN and 0.62 (95% CI: 0.54; 0.70) for AUD. Unique environmental factors accounted for the remainder of variance for BN. The genetic correlation between BN and AUD was 0.23 (95% CI: 0.01; 0.44), and the correlation between the unique environmental factors for the two disorders was 0.35 (95% CI: 0.08; 0.61), suggesting moderate overlap in these factors. Findings from this investigation provide additional support that some of the same genetic factors may influence liability to both BN and AUD.
doi:10.1016/j.psychres.2013.04.030
PMCID: PMC3736835  PMID: 23790978
bivariate; comorbidity; twin study
17.  Fetal and Maternal Genes’ Influence on Gestational Age in a Quantitative Genetic Analysis of 244,000 Swedish Births 
American Journal of Epidemiology  2013;178(4):543-550.
Although there is increasing evidence that genetic factors influence gestational age, it is unclear to what extent this is due to fetal and/or maternal genes. In this study, we apply a novel analytical model to estimate genetic and environmental contributions to pregnancy history records obtained from 165,952 Swedish families consisting of offspring of twins, full siblings, and half-siblings (1987–2008). Results indicated that fetal genetic factors explained 13.1% (95% confidence interval (CI): 6.8, 19.4) of the variation in gestational age at delivery, while maternal genetic factors accounted for 20.6% (95% CI: 18.1, 23.2). The largest contribution to differences in the timing of birth were environmental factors, of which 10.1% (95% CI: 7.0, 13.2) was due to factors shared by births of the same mother, and 56.2% (95% CI: 53.0, 59.4) was pregnancy specific. Similar models fit to the same data dichotomized at clinically meaningful thresholds (e.g., preterm birth) resulted in less stable parameter estimates, but the collective results supported a model of homogeneous genetic and environmental effects across the range of gestational age. Since environmental factors explained most differences in the timing of birth, genetic studies may benefit from understanding the specific effect of fetal and maternal genes in the context of these yet-unidentified factors.
doi:10.1093/aje/kwt005
PMCID: PMC3736752  PMID: 23568591
environment; fetal genes; gestational age; maternal genes; preterm birth; twins
18.  Violent crime, suicide, and premature mortality in patients with schizophrenia and related disorders: a 38-year total population study in Sweden 
The lancet psychiatry  2014;1(1):44-54.
Summary
Background
People with schizophrenia and related disorders are at an increased risk of adverse outcomes, including conviction of a violent offence, suicide, and premature mortality. However, the rates of, and risk factors for, these outcomes need clarification as a basis for population-based and targeted interventions. We aimed to determine rates and risk factors for these outcomes, and investigate to what extent they are shared across outcomes and are specific to schizophrenia and related disorders.
Methods
We undertook a total population cohort study in Sweden of 24 297 patients with schizophrenia and related disorders between January, 1972 and December, 2009. Patients were matched by age and sex to people from the general population (n=485 940) and also to unaffected sibling controls (n=26 357). First, we investigated rates of conviction of a violent offence, suicide, and premature mortality, with follow-up until conviction of a violent offence, emigration, death, or end of follow-up (Dec 31, 2009), whichever occurred first. Second, we analysed associations between these adverse outcomes and sociodemographic, individual, familial, and distal risk factors, for men and women separately, with Cox proportional hazards models. Finally, we assessed time trends in adverse outcomes between 1972 and 2009, for which we compared patients with unaffected siblings, and analysed associations with changes in the number of nights spent in inpatient beds in psychiatric facilities nationwide.
Findings
Within 5 years of their initial diagnosis, 13·9% of men and 4·7% of women with schizophrenia and related disorders had a major adverse outcome (10·7% of men and 2·7% of women were convicted of a violent offence, and 3·3% of men and 2·0% of women died prematurely of any cause). During the study, the adjusted odds ratio of any adverse outcomes for patients compared with general population controls was 7·5 (95% CI 7·2–7·9) in men and 11·1 (10·2–12·1) in women. Three risk factors that were present before diagnosis were predictive of any adverse outcome: drug use disorders, criminality, and self-harm, which were also risk factors for these outcomes in unaffected siblings and in the general population. Over the period 1973–2009, the odds of these outcomes increased in patients with schizophrenia and related disorders compared with unaffected siblings.
Interpretation
Schizophrenia and related disorders are associated with substantially increased rates of violent crime, suicide, and premature mortality. Risk factors for these three outcomes included both those specific to individuals with schizophrenia and related disorders, and those shared with the general population. Therefore, a combination of population-based and targeted strategies might be necessary to reduce the substantial rates of adverse outcomes in patients with schizophrenia and related disorders.
doi:10.1016/S2215-0366(14)70223-8
PMCID: PMC4124855  PMID: 25110636
19.  The impact of neighbourhood deprivation on adolescent violent criminality and substance misuse: A longitudinal, quasi-experimental study of the total Swedish population 
Background A number of studies suggest associations between neighbourhood characteristics and criminality during adolescence and young adulthood. However, the causality of such neighbourhood effects remains uncertain.
Methods We followed all children born in Sweden from 1975–1989 who lived in its three largest cities by the age of 15 years and for whom complete information was available about individual and contextual factors (N = 303 465). All biological siblings were identified in the sample (N = 179 099). Generalized linear mixed-effects models were used to assess the effect of neighbourhood deprivation on violent criminality and substance misuse between the ages of 15 and 20 years, while taking into account the cross-classified data structure (i.e. siblings in the same families attending different schools and living in different neighbourhoods at age 15).
Results In the crude model, an increase of 1 SD in neighbourhood deprivation was associated with a 57% increase in the odds of being convicted of a violent crime (95% CI 52%–63%). The effect was greatly attenuated when adjustment was made for a number of observed confounders (OR 1.09, 95% CI 1.06–1.11). When we additionally adjusted for unobserved familial confounders, the effect was no longer present (OR 0.96, 95% CI 0.84–1.10). Similar results were observed for substance misuse. The results were not due to poor variability either between neighbourhoods or within families.
Conclusions We found that the adverse effect of neighbourhood deprivation on adolescent violent criminality and substance misuse in Sweden was not consistent with a causal inference. Instead, our findings highlight the need to control for familial confounding in multilevel studies of criminality and substance misuse.
doi:10.1093/ije/dyt066
PMCID: PMC3780994  PMID: 24062294
Violence; substance-related disorders; residence characteristics; socio-economic factors; multi-level analysis; confounding factors
20.  Does attention deficit hyperactivity disorder share etiologic factors with bipolar disorder and schizophrenia? 
BACKGROUND
ADHD is associated with bipolar disorder and schizophrenia, and it has been suggested that combined bipolar disorder/ADHD is etiologically distinct from the pure disorders.
AIM
To clarify if ADHD shares genetic and environmental factors with bipolar disorder and schizophrenia.
METHODS
By linking longitudinal Swedish national registers, we identified 61,187 ADHD probands and their first and second-degree relatives and matched them with non-ADHD controls and their corresponding relatives. Conditional logistic regression was used to determine risks for bipolar disorder and schizophrenia in relatives of probands vs. controls.
RESULTS
First-degree relatives of ADHD probands were at increased risk of both bipolar disorder (ORs from 1.84 to 2.54 for parents, offspring and full siblings) and schizophrenia (ORs from 1.71 to 2.22 for parents, offspring and full siblings). The risk of bipolar disorder and schizophrenia among second-degree relatives were substantially lower than among full-siblings.
CONCLUSIONS
These findings suggest that co-occurring ADHD and bipolar disorder and ADHD plus schizophrenia are due to shared genetic factors, rather than representing completely etiologically distinct sub-syndromes.
doi:10.1192/bjp.bp.112.120808
PMCID: PMC3730113  PMID: 23703314
ADHD; Bipolar disorder; Schizophrenia; Comorbidity; Family study
21.  Maternal stress and infant mortality: The importance of the preconception period 
Psychological science  2013;24(7):1309-1316.
Although preconception and prenatal maternal stress are associated with adverse birth and childhood outcomes, the relation to infant mortality remains uncertain. We used logistic regression to study infant mortality risk following maternal stress within a population-based sample of offspring born in Sweden from 1973 to 2008 (N= 3,055,361). Preconception (6-0 months before conception) and prenatal (conception to birth) stress was defined as death of a first-degree relative of the mother. A total of 20,651 offspring were exposed to preconception stress, 26,731 to prenatal stress, and 8,398 cases of infant mortality were identified. Preconception stress increased the risk of infant mortality independent of measured covariates (adjusted OR=1.53; 95% CI=1.25–1.88) and the association was timing-specific and robust across low-risk groups. Prenatal stress did not increase risk of infant mortality (adjusted OR=1.05; 95% CI=0.84–1.30). The period immediately before conception may be a sensitive developmental period influencing risk for infant mortality.
doi:10.1177/0956797612468010
PMCID: PMC3713176  PMID: 23653129
Preconception; prenatal; maternal stress; bereavement; infant mortality
22.  Suicide, Fatal Injuries, and Other Causes of Premature Mortality in Patients With Traumatic Brain Injury 
JAMA psychiatry  2014;71(3):326-333.
IMPORTANCE
Longer-term mortality in individuals who have survived a traumatic brain injury (TBI) is not known.
OBJECTIVES
To examine the relationship between TBI and premature mortality, particularly by external causes, and determine the role of psychiatric comorbidity.
DESIGN, SETTING, AND PATIENTS
We studied all persons born in 1954 or later in Sweden who received inpatient and outpatient International Classification of Diseases-based diagnoses of TBI from 1969 to 2009 (n = 218 300). We compared mortality rates 6 months or more after TBI to general population controls matched on age and sex (n = 2 163 190) and to unaffected siblings of patients with TBI (n = 150 513). Furthermore, we specifically examined external causes of death (suicide, injury, or assault). We conducted sensitivity analyses to investigate whether mortality rates differed by sex, age at death, severity (including concussion), and different follow-up times after diagnosis.
MAIN OUTCOMES AND MEASURES
Adjusted odds ratios (AORs) of premature death by external causes in patients with TBI compared with general population controls.
RESULTS
Among those who survived 6 months after TBI, we found a 3-fold increased odds of mortality (AOR, 3.2; 95% CI, 3.0-3.4) compared with general population controls and an adjusted increased odds of mortality of 2.6 (95% CI, 2.3-2.8) compared with unaffected siblings. Risks of mortality from external causes were elevated, including for suicide (AOR, 3.3; 95% CI, 2.9-3.7), injuries (AOR, 4.3; 95% CI, 3.8-4.8), and assault (AOR, 3.9; 95% CI, 2.7-5.7). Among those with TBI, absolute rates of death were high in those with any psychiatric or substance abuse comorbidity (3.8% died prematurely) and those with solely substance abuse (6.2%) compared with those without comorbidity (0.5%).
CONCLUSIONS AND RELEVANCE
Traumatic brain injury is associated with substantially elevated risks of premature mortality, particularly for suicide, injuries, and assaults, even after adjustment for sociodemographic and familial factors. Current clinical guidelines may need revision to reduce mortality risks beyond the first few months after injury and address high rates of psychiatric comorbidity and substance abuse.
doi:10.1001/jamapsychiatry.2013.3935
PMCID: PMC4058552  PMID: 24430827
23.  Intrauterine testosterone exposure and risk for disordered eating 
Summary
Previous research has suggested that prenatal testosterone exposure masculinises disordered eating by comparing opposite- and same-gender twins. The objective of the current study is to replicate this finding using a sample of 439 identical and 213 fraternal females, 461 identical and 344 fraternal males, and 361 males and 371 females from opposite-gender twin pairs. Disordered eating was compared across twin types using the Eating Disorder Inventory–2. Inconsistent with previous findings, a main effect of co-twin gender was not found. Our results raise questions about the validity of prior evidence of the impact of prenatal testosterone exposure on patterns of disordered eating.
doi:10.1192/bjp.bp.108.054692
PMCID: PMC4059089  PMID: 19336794
24.  Genetic Risk Factors for Disordered Eating in Adolescent Males and Females 
Journal of abnormal psychology  2009;118(3):576-586.
The etiologic role of genetic and environmental factors on disordered eating was examined in a sample of 15- to 17-year-old female–female, male–male, and opposite-sex twin pairs. Also assessed was whether a single factor is underlying 3 facets (body dissatisfaction, drive for thinness, bulimia) of disordered eating, including the possible importance of sex differences. Univariate model-fitting analyses indicated that genetic factors are more important for girls and environment more important for boys for body dissatisfaction and drive for thinness. A multivariate common factor analysis indicated that a single factor accounted for the association among these 3 facets of disordered eating in both sexes. However, only 50% of the genetic risk for this factor is shared between the sexes.
doi:10.1037/a0016314
PMCID: PMC4045449  PMID: 19685954
eating disorder; disordered eating; twin study; genetics; sex differences
25.  The association between teenage motherhood and poor offspring outcomes: A national cohort study across 30 years 
Teenage motherhood is associated with poor offspring outcomes but these associations may be influenced by offspring birth year because of substantial social changes in recent decades. Existing research also has not examined whether these associations are due to the specific effect of mother’s age at childbirth or factors shared by siblings in a family. We used a population-based cohort study in Sweden comprising all children born from 1960–1989 (N=3,162,239), and a subsample of siblings differentially exposed to maternal teenage childbearing (N=485,259) to address these limitations. We examined the effect of teenage childbearing on offspring violent and nonviolent criminal convictions, poor academic performance, and substance-related problems. Population-wide, teenage childbearing was associated with offspring criminal convictions, poor academic performance, and substance-related problems. The magnitude of these associations increased over time. Comparisons of differentially exposed siblings indicated no within-family association between teenage childbearing and offspring violent and nonviolent criminal convictions or poor academic performance, although offspring born to teenage mothers were more likely to experience substance-related problems than their later-born siblings. Being born to a teenage mother in Sweden has become increasingly associated with negative outcomes across time, but the nature of this association may differ by outcome. Teenage childbearing may be associated with offspring violent and nonviolent criminal convictions and poor academic performance because of shared familial risk factors but may be causally associated with offspring substance-related problems. The findings suggest that interventions to improve offspring outcomes should delay teenage childbearing and target risk factors influencing all offspring of teenage mothers.
doi:10.1017/thg.2013.23
PMCID: PMC3657321  PMID: 23632141
Teenage childbearing; teenage motherhood; criminal behavior; substance use; academic attainment; academic achievement

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