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1.  Autism and epilepsy 
Neurology  2016;87(2):192-197.
Objective:
To investigate the risk of autism spectrum disorder (ASD) in individuals with epilepsy and in their first-degree relatives to determine shared etiology.
Methods:
Through the Swedish Patient Register, we identified 85,201 individuals with epilepsy, as well as all their siblings (n = 80,511) and offspring (n = 98,534). Each individual with epilepsy was compared with 5 controls, matched for age, sex, calendar period, and county, while siblings and offspring were compared with siblings and offspring of controls. We excluded siblings and offspring with epilepsy. Using Cox regression, we calculated hazard ratios (HRs) for future diagnosis of ASD. Logistic regression was applied to calculate odds ratios (ORs) for prior diagnosis of ASD.
Results:
During follow-up, 1,381 (1.6%) individuals with epilepsy and 700 (0.2%) controls were diagnosed with ASD. Individuals with epilepsy were therefore at increased risk of future ASD (HR 10.49, 95% confidence interval [CI] 9.55–11.53), with the highest risk seen in individuals diagnosed with epilepsy in childhood. Both siblings (HR 1.62, 95% CI 1.43–1.83) and offspring (HR 1.64, 95% CI 1.46–1.84) of epilepsy patients were at increased risk of ASD. The risk in the offspring was particularly high in mothers with epilepsy (HR 1.91; 95% CI 1.63–2.23). Epilepsy was also associated with a prior diagnosis of ASD (OR 4.56, 95% CI 4.02–5.18).
Conclusions:
Individuals with epilepsy are at increased risk of ASD, especially if epilepsy appears in childhood. Further, ASD is more common in the siblings and offspring of individuals with epilepsy, suggesting shared etiology.
doi:10.1212/WNL.0000000000002836
PMCID: PMC4940061  PMID: 27306624
2.  Associations between the parent–child relationship and adolescent self‐worth: a genetically informed study of twin parents and their adolescent children 
Background
Low self‐worth during adolescence predicts a range of emotional and behavioural problems. As such, identifying potential sources of influence on self‐worth is important. Aspects of the parent–child relationship are often associated with adolescent self‐worth but to date it is unclear whether such associations may be attributable to familial confounding (e.g. genetic relatedness). We set out to clarify the nature of relationships between parental expressed affection and adolescent self‐worth, and parent–child closeness and adolescent self‐worth.
Methods
We used data from the Twin and Offspring Study in Sweden, a children‐of‐twins sample comprising 909 adult twin pairs with adolescent children. Using these data we were able to apply structural equation models with which we could examine whether associations remained after accounting for genetic transmission.
Results
Results demonstrated that parent–child closeness and parental‐expressed affection were both phenotypically associated with adolescent self‐worth. Associations could not be attributed to genetic relatedness between parent and child.
Conclusions
Parent–child closeness and parental affection are associated with adolescent self‐worth above and beyond effects attributable to genetic relatedness. Data were cross‐sectional, so the direction of effects cannot be confirmed but findings support the notion that positive parent–child relationships increase adolescent self‐worth.
doi:10.1111/jcpp.12600
PMCID: PMC5215430  PMID: 27426633
Adolescence; parenting; parent–child relationships; children‐of‐twins; self‐esteem
3.  Genetic and environmental influences on adult human height across birth cohorts from 1886 to 1994 
Jelenkovic, Aline | Hur, Yoon-Mi | Sund, Reijo | Yokoyama, Yoshie | Siribaddana, Sisira H | Hotopf, Matthew | Sumathipala, Athula | Rijsdijk, Fruhling | Tan, Qihua | Zhang, Dongfeng | Pang, Zengchang | Aaltonen, Sari | Heikkilä, Kauko | Öncel, Sevgi Y | Aliev, Fazil | Rebato, Esther | Tarnoki, Adam D | Tarnoki, David L | Christensen, Kaare | Skytthe, Axel | Kyvik, Kirsten O | Silberg, Judy L | Eaves, Lindon J | Maes, Hermine H | Cutler, Tessa L | Hopper, John L | Ordoñana, Juan R | Sánchez-Romera, Juan F | Colodro-Conde, Lucia | Cozen, Wendy | Hwang, Amie E | Mack, Thomas M | Sung, Joohon | Song, Yun-Mi | Yang, Sarah | Lee, Kayoung | Franz, Carol E | Kremen, William S | Lyons, Michael J | Busjahn, Andreas | Nelson, Tracy L | Whitfield, Keith E | Kandler, Christian | Jang, Kerry L | Gatz, Margaret | Butler, David A | Stazi, Maria A | Fagnani, Corrado | D'Ippolito, Cristina | Duncan, Glen E | Buchwald, Dedra | Derom, Catherine A | Vlietinck, Robert F | Loos, Ruth JF | Martin, Nicholas G | Medland, Sarah E | Montgomery, Grant W | Jeong, Hoe-Uk | Swan, Gary E | Krasnow, Ruth | Magnusson, Patrik KE | Pedersen, Nancy L | Dahl-Aslan, Anna K | McAdams, Tom A | Eley, Thalia C | Gregory, Alice M | Tynelius, Per | Baker, Laura A | Tuvblad, Catherine | Bayasgalan, Gombojav | Narandalai, Danshiitsoodol | Lichtenstein, Paul | Spector, Timothy D | Mangino, Massimo | Lachance, Genevieve | Bartels, Meike | van Beijsterveldt, Toos CEM | Willemsen, Gonneke | Burt, S Alexandra | Klump, Kelly L | Harris, Jennifer R | Brandt, Ingunn | Nilsen, Thomas Sevenius | Krueger, Robert F | McGue, Matt | Pahlen, Shandell | Corley, Robin P | Hjelmborg, Jacob v B | Goldberg, Jack H | Iwatani, Yoshinori | Watanabe, Mikio | Honda, Chika | Inui, Fujio | Rasmussen, Finn | Huibregtse, Brooke M | Boomsma, Dorret I | Sørensen, Thorkild I A | Kaprio, Jaakko | Silventoinen, Karri
eLife  null;5:e20320.
Human height variation is determined by genetic and environmental factors, but it remains unclear whether their influences differ across birth-year cohorts. We conducted an individual-based pooled analysis of 40 twin cohorts including 143,390 complete twin pairs born 1886–1994. Although genetic variance showed a generally increasing trend across the birth-year cohorts, heritability estimates (0.69-0.84 in men and 0.53-0.78 in women) did not present any clear pattern of secular changes. Comparing geographic-cultural regions (Europe, North America and Australia, and East Asia), total height variance was greatest in North America and Australia and lowest in East Asia, but no clear pattern in the heritability estimates across the birth-year cohorts emerged. Our findings do not support the hypothesis that heritability of height is lower in populations with low living standards than in affluent populations, nor that heritability of height will increase within a population as living standards improve.
DOI: http://dx.doi.org/10.7554/eLife.20320.001
doi:10.7554/eLife.20320
PMCID: PMC5156525  PMID: 27964777
height; twins; heritability; birth cohorts; CODATwins project; Human
4.  Genome-wide association study identifies 74 loci associated with educational attainment 
Okbay, Aysu | Beauchamp, Jonathan P. | Fontana, Mark A. | Lee, James J. | Pers, Tune H. | Rietveld, Cornelius A. | Turley, Patrick | Chen, Guo-Bo | Emilsson, Valur | Meddens, S. Fleur W. | Oskarsson, Sven | Pickrell, Joseph K. | Thom, Kevin | Timshel, Pascal | de Vlaming, Ronald | Abdellaoui, Abdel | Ahluwalia, Tarunveer S. | Bacelis, Jonas | Baumbach, Clemens | Bjornsdottir, Gyda | Brandsma, Johannes H. | Concas, Maria Pina | Derringer, Jaime | Furlotte, Nicholas A. | Galesloot, Tessel E. | Girotto, Giorgia | Gupta, Richa | Hall, Leanne M. | Harris, Sarah E. | Hofer, Edith | Horikoshi, Momoko | Huffman, Jennifer E. | Kaasik, Kadri | Kalafati, Ioanna P. | Karlsson, Robert | Kong, Augustine | Lahti, Jari | van der Lee, Sven J. | de Leeuw, Christiaan | Lind, Penelope A. | Lindgren, Karl-Oskar | Liu, Tian | Mangino, Massimo | Marten, Jonathan | Mihailov, Evelin | Miller, Michael B. | van der Most, Peter J. | Oldmeadow, Christopher | Payton, Antony | Pervjakova, Natalia | Peyrot, Wouter J. | Qian, Yong | Raitakari, Olli | Rueedi, Rico | Salvi, Erika | Schmidt, Börge | Schraut, Katharina E. | Shi, Jianxin | Smith, Albert V. | Poot, Raymond A. | Pourcain, Beate | Teumer, Alexander | Thorleifsson, Gudmar | Verweij, Niek | Vuckovic, Dragana | Wellmann, Juergen | Westra, Harm-Jan | Yang, Jingyun | Zhao, Wei | Zhu, Zhihong | Alizadeh, Behrooz Z. | Amin, Najaf | Bakshi, Andrew | Baumeister, Sebastian E. | Biino, Ginevra | Bønnelykke, Klaus | Boyle, Patricia A. | Campbell, Harry | Cappuccio, Francesco P. | Davies, Gail | De Neve, Jan-Emmanuel | Deloukas, Panos | Demuth, Ilja | Ding, Jun | Eibich, Peter | Eisele, Lewin | Eklund, Niina | Evans68, David M. | Faul, Jessica D. | Feitosa, Mary F. | Forstner, Andreas J. | Gandin, Ilaria | Gunnarsson, Bjarni | Halldórsson, Bjarni V. | Harris, Tamara B. | Heath, Andrew C. | Hocking, Lynne J. | Holliday, Elizabeth G. | Homuth, Georg | Horan, Michael A. | Hottenga, Jouke-Jan | de Jager, Philip L. | Joshi, Peter K. | Jugessur, Astanand | Kaakinen, Marika A. | Kähönen, Mika | Kanoni, Stavroula | Keltigangas-Järvinen, Liisa | Kiemeney, Lambertus A.L.M. | Kolcic, Ivana | Koskinen, Seppo | Kraja, Aldi T. | Kroh, Martin | Kutalik, Zoltan | Latvala, Antti | Launer, Lenore J. | Lebreton, Maël P. | Levinson, Douglas F. | Lichtenstein, Paul | Lichtner, Peter | Liewald, David C.M. | Loukola, Anu | Madden, Pamela A. | Mägi, Reedik | Mäki-Opas, Tomi | Marioni, Riccardo E. | Marques-Vidal, Pedro | Meddens, Gerardus A. | McMahon, George | Meisinger, Christa | Meitinger, Thomas | Milaneschi, Yusplitri | Milani, Lili | Montgomery, Grant W. | Myhre, Ronny | Nelson, Christopher P. | Nyholt, Dale R. | Ollier, William E.R. | Palotie, Aarno | Paternoster, Lavinia | Pedersen, Nancy L. | Petrovic, Katja E. | Porteous, David J. | Räikkönen, Katri | Ring, Susan M. | Robino, Antonietta | Rostapshova, Olga | Rudan, Igor | Rustichini, Aldo | Salomaa, Veikko | Sanders, Alan R. | Sarin, Antti-Pekka | Schmidt, Helena | Scott, Rodney J. | Smith, Blair H. | Smith, Jennifer A. | Staessen, Jan A. | Steinhagen-Thiessen, Elisabeth | Strauch, Konstantin | Terracciano, Antonio | Tobin, Martin D. | Ulivi, Sheila | Vaccargiu, Simona | Quaye, Lydia | van Rooij, Frank J.A. | Venturini, Cristina | Vinkhuyzen, Anna A.E. | Völker, Uwe | Völzke, Henry | Vonk, Judith M. | Vozzi, Diego | Waage, Johannes | Ware, Erin B. | Willemsen, Gonneke | Attia, John R. | Bennett, David A. | Berger, Klaus | Bertram, Lars | Bisgaard, Hans | Boomsma, Dorret I. | Borecki, Ingrid B. | Bultmann, Ute | Chabris, Christopher F. | Cucca, Francesco | Cusi, Daniele | Deary, Ian J. | Dedoussis, George V. | van Duijn, Cornelia M. | Eriksson, Johan G. | Franke, Barbara | Franke, Lude | Gasparini, Paolo | Gejman, Pablo V. | Gieger, Christian | Grabe, Hans-Jörgen | Gratten, Jacob | Groenen, Patrick J.F. | Gudnason, Vilmundur | van der Harst, Pim | Hayward, Caroline | Hinds, David A. | Hoffmann, Wolfgang | Hyppönen, Elina | Iacono, William G. | Jacobsson, Bo | Järvelin, Marjo-Riitta | Jöckel, Karl-Heinz | Kaprio, Jaakko | Kardia, Sharon L.R. | Lehtimäki, Terho | Lehrer, Steven F. | Magnusson, Patrik K.E. | Martin, Nicholas G. | McGue, Matt | Metspalu, Andres | Pendleton, Neil | Penninx, Brenda W.J.H. | Perola, Markus | Pirastu, Nicola | Pirastu, Mario | Polasek, Ozren | Posthuma, Danielle | Power, Christine | Province, Michael A. | Samani, Nilesh J. | Schlessinger, David | Schmidt, Reinhold | Sørensen, Thorkild I.A. | Spector, Tim D. | Stefansson, Kari | Thorsteinsdottir, Unnur | Thurik, A. Roy | Timpson, Nicholas J. | Tiemeier, Henning | Tung, Joyce Y. | Uitterlinden, André G. | Vitart, Veronique | Vollenweider, Peter | Weir, David R. | Wilson, James F. | Wright, Alan F. | Conley, Dalton C. | Krueger, Robert F. | Smith, George Davey | Hofman, Albert | Laibson, David I. | Medland, Sarah E. | Meyer, Michelle N. | Yang, Jian | Johannesson, Magnus | Visscher, Peter M. | Esko, Tõnu | Koellinger, Philipp D. | Cesarini, David | Benjamin, Daniel J.
Nature  2016;533(7604):539-542.
Summary
Educational attainment (EA) is strongly influenced by social and other environmental factors, but genetic factors are also estimated to account for at least 20% of the variation across individuals1. We report the results of a genome-wide association study (GWAS) for EA that extends our earlier discovery sample1,2 of 101,069 individuals to 293,723 individuals, and a replication in an independent sample of 111,349 individuals from the UK Biobank. We now identify 74 genome-wide significant loci associated with number of years of schooling completed. Single-nucleotide polymorphisms (SNPs) associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioral phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because EA is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric disease.
doi:10.1038/nature17671
PMCID: PMC4883595  PMID: 27225129
5.  Patterns of Nonrandom Mating Within and Across 11 Major Psychiatric Disorders 
JAMA psychiatry  2016;73(4):354-361.
IMPORTANCE
Psychiatric disorders are heritable, polygenic traits, which often share risk alleles and for which nonrandom mating has been suggested. However, despite the potential etiological implications, the scale of nonrandom mating within and across major psychiatric conditions remains unclear.
OBJECTIVE
To quantify the nature and extent of nonrandom mating within and across a broad range of psychiatric conditions at the population level.
DESIGN, SETTING, AND PARTICIPANTS
Population-based cohort using Swedish population registers. Participants were all Swedish residents with a psychiatric diagnosis of interest (attention-deficit/hyperactivity disorder, autism spectrum disorder, schizophrenia, bipolar disorder, major depression, generalized anxiety disorder, agoraphobia, social phobia, obsessive-compulsive disorder, anorexia, or substance abuse), along with their mates. Individuals with select nonpsychiatric disorders (Crohn’s disease, type 1 and type 2 diabetes mellitus, multiple sclerosis, or rheumatoid arthritis) were included for comparison. General population samples were also derived and matched 1:5 with each case proband. Inpatient and outpatient diagnostic data were derived from the Swedish National Patient Register (1973-2009), with analyses conducted between June 2014 and May 2015.
MAIN OUTCOMES AND MEASURES
Correlation in the diagnostic status of mates both within and across disorders. Conditional logistic regression was used to quantify the odds of each diagnosis in the mates of cases relative to matched population controls.
RESULTS
Across cohorts, data corresponded to 707 263 unique case individuals, with women constituting 45.7% of the full population. Positive correlations in diagnostic status were evident between mates. Within-disorder correlations were marginally higher (range, 0.11-0.48) than cross-disorder correlations (range, 0.01-0.42). Relative to matched populations, the odds of psychiatric case probands having an affected mate were significantly elevated. Differences in the magnitude of observed relationships were apparent by disorder (odds ratio range, 0.8-11.4). The number of comorbidities in a case proband was associated with the proportion of affected mates. These relationships were not apparent or weaker in magnitude among nonpsychiatric conditions (correlation range, −0.03 to 0.17).
CONCLUSIONS AND RELEVANCE
Nonrandom mating is evident in psychiatric populations both within specific disorders and across the spectrum of psychiatric conditions. This phenomenon may hold important implications for how we understand the familial transmission of these disorders and for psychiatric genetic research.
doi:10.1001/jamapsychiatry.2015.3192
PMCID: PMC5082975  PMID: 26913486
6.  Sex- and Age-Specific Incidence of Healthcare-Register-Recorded Eating Disorders in the Complete Swedish 1979–2001 Birth Cohort 
Objective
To investigate the sex- and age-specific incidence of healthcare-register-recorded anorexia nervosa (AN) and other eating disorders (OED) in a complete birth cohort, and assess whether incidence varies by diagnostic period and (sub-) birth cohort.
Method
We used the actuarial method and Poisson models to examine the incidence of AN and OED from 1987–2009 (when individuals were 8–30 years) for a cohort of 2.3 million individuals (48.7% female) born from 1979–2001 in Sweden, identified using Swedish registers.
Results
For both sexes, incidences of AN and OED increased considerably for diagnostic periods after 2000, but differed little by birth cohort. In 2009, AN incidence in the peak age category was 205.9 cases/100,000 persons (95% CI: 178.2, 233.5) for females (14–15 years), versus 12.8 cases/100,000 (95% CI: 5.6, 20.1) for males (12–13 years). OED incidence in the peak age category was 372.1 cases/100,000 (95% CI: 336.4, 407.9) for females (16–17 years), versus 22.2 cases/100,000 (95% CI: 13.3, 31.1) for males (14–15 years).
Discussion
Our finding of an increase in healthcare register-recorded eating disorders for diagnostic periods after 2000 likely reflects improved detection and expanded register coverage in Sweden. The peak of eating disorder incidence in adolescence, which began unexpectedly early for AN in males, suggests the importance of vigilance for signs of AN in young boys and early primary prevention efforts. Waiting until later could miss critical windows for intervention that could prevent disorders from taking root.
doi:10.1002/eat.22467
PMCID: PMC5028825  PMID: 26769444
eating disorders; anorexia nervosa; men; incidence; epidemiology; Sweden
7.  Obsessive-Compulsive Disorder, Psychosis, and Bipolarity: A Longitudinal Cohort and Multigenerational Family Study 
Schizophrenia Bulletin  2014;41(5):1076-1083.
Obsessive-compulsive disorder (OCD) often co-occurs with psychotic and bipolar disorders; this comorbidity complicates the clinical management of these conditions. In this population-based longitudinal and multigenerational family study, we examined the patterns of comorbidity, longitudinal risks, and shared familial risks between these disorders. Participants were individuals with a diagnosis of OCD (n = 19814), schizophrenia (n = 58336), bipolar disorder (n = 48180), and schizoaffective disorder (n = 14904) included in the Swedish Patient Register between January 1969 and December 2009; their first-, second-, and third-degree relatives; and population-matched (1:10 ratio) unaffected comparison individuals and their relatives. The Swedish Prescribed Drug Register was used to control for the potential effect of medication in the longitudinal analyses. Individuals with OCD had a 12-fold increased risk of having a comorbid diagnosis of schizophrenia and a 13-fold increased risk of bipolar disorder and schizoaffective disorder. Longitudinal analyses showed that individuals first diagnosed with OCD had an increased risk for later diagnosis of all other disorders, and vice versa. The risk of bipolar disorder was reduced, but not eliminated, when the use of selective serotonin reuptake inhibitors was adjusted for. OCD-unaffected first-, second-, and third-degree relatives of probands with OCD had a significantly increased risk for all 3 disorders; the magnitude of this risk decreased as the genetic distance increased. We conclude that OCD is etiologically related to both schizophrenia spectrum and bipolar disorders. The results have implications for current gene-searching efforts and for clinical practice.
doi:10.1093/schbul/sbu169
PMCID: PMC4535627  PMID: 25512596
OCD; schizophrenia; schizoaffective disorder; bipolar disorder; genetic epidemiology
8.  Risk for self-reported anorexia or bulimia nervosa based on drive for thinness and negative affect clusters/dimensions during adolescence: A three-year prospective study of the TChAD cohort 
Objective
The present study explored the cross-sectional and predictive effect of drive for thinness and/or negative affect scores on the development of self-reported anorexia nervosa (AN) and bulimia nervosa (BN).
Method
K-means were used to cluster the Eating Disorder Inventory-Drive for Thinness (DT) and Child Behavior Checklist Anxious/Depressed (A/D) scores from 615 unrelated female twins at age 16–17. Logistic regressions were used to assess the effect of these clusters on self-reported eating disorder diagnosis at ages 16–17 (n=565) and 19–20 (n=451).
Results
DT and A/D scores were grouped into four clusters: Mild (scores lower than 90th percentile on both scales), DT (higher scores only on DT), A/D (higher scores only on A/D), and DT-A/D (higher scores on both the DT and A/D scales). DT and DT-A/D clusters at age 16–17 were associated cross-sectionally with AN and both cross-sectionally and longitudinally with BN. The DT-A/D cluster had the highest prevalence of AN at follow-up compared with all other clusters. Similarly, an interaction was observed between DT and A/D that predicted risk for AN.
Discussion
Having elevated DT and A/D scores may increase risk for eating disorder symptomatology above and beyond a high score on either alone. Findings suggest that cluster modeling based on DT and A/D may be useful to inform novel and useful intervention strategies for AN and BN in adolescents.
doi:10.1002/eat.22431
PMCID: PMC4543580  PMID: 26013185
Drive for thinness; anxiety; depression; negative affect; subtyping; eating disorders; anorexia; bulimia; risk
9.  Is physical activity causally associated with symptoms of attention-deficit/ hyperactivity disorder? 
Objective
Emerging evidence suggests that physical activity (PA) enhances cognition and may be a protective factor for attention-deficit/ hyperactivity disorder (ADHD). Yet, the impact of PA on ADHD symptoms has only been investigated in a few undersized, non-randomised and retrospective studies. We examined the effect of PA during late adolescence on ADHD symptoms in early adulthood while controlling for unmeasured genetic and shared environmental confounding.
Methods
The effect of PA at age 16-17 (baseline) on ADHD symptoms at age 19-20 (follow-up) was examined using a within-monozygotic twins fixed-effects model in 232 monozygotic twin pairs born in Sweden between May 1985 and December 1986. Parents rated their children’s DSM ADHD symptoms at baseline and follow-up. Participants’ weekly energy expenditure (in metabolic equivalent task minutes/ week) was based on self-reports at baseline of PA frequency, intensity and duration.
Results
Greater weekly energy expenditure in adolescence was significantly associated with reduced ADHD symptom levels in early adulthood, even when controlling for unmeasured confounding (all genetic and shared environmental factors shared within MZ twin pairs) and ADHD symptoms and BMI at baseline, β = - 0.21, p=0.013 (95% CI= -0.38 – -0.05). Similar results were observed for the two ADHD sub-components; hyperactivity/ impulsivity, β = -0.21, p=0.022 (95% CI= -0.39 – -0.03), and inattention, β = -0.19, p=0.049 (95% CI= -0.36 – -0.0005).
Conclusion
In line with a causal hypothesis, PA was inversely associated with ADHD symptoms, even after adjusting for unmeasured confounding. These findings suggest that PA in adolescence might decrease ADHD symptoms in early adulthood. However, given the size of the effect, the clinical value of this intervention needs to be explored further.
doi:10.1016/j.jaac.2015.04.011
PMCID: PMC4984951  PMID: 26088661
Physical activity; ADHD; exercise; twin modelling; TCHAD
10.  Adolescent Age Moderates Genetic and Environmental Influences on Parent-Adolescent Positivity and Negativity: Implications for Genotype-Environment Correlation 
Development and psychopathology  2015;28(1):149-166.
In the present study we examined how genotype-environment correlation processes differ as a function of adolescent age. We tested whether adolescent age moderates genetic and environmental influences on positivity and negativity in mother-adolescent and father-adolescent relationships using parallel samples of twin parents from the Twin and Offspring Study in Sweden and twin/sibling adolescents from the Nonshared Environment in Adolescent Development Study. We inferred differences in the role of passive and non-passive genotype-environment correlation based on biometric moderation findings. Findings indicated that non-passive rGE played a stronger role for positivity in mother- and father- adolescent relationships in families with older adolescents than families with younger adolescents, and that passive rGE played a stronger role for positivity in the mother-adolescent relationship in families with younger adolescents than in families with older adolescents. Implications of these findings for the timing and targeting of interventions on family relationships are discussed.
doi:10.1017/S0954579415000358
PMCID: PMC4627902  PMID: 25924807
Parent-adolescent relationship; Genotype-environment correlation; age; developmental differences
11.  Nationwide population-based cohort study of psychiatric disorders in individuals with Ehlers–Danlos syndrome or hypermobility syndrome and their siblings 
BMC Psychiatry  2016;16:207.
Background
To assess the risk of psychiatric disorders in Ehlers-Danlos syndrome (EDS) and hypermobility syndrome.
Methods
Nationwide population-based matched cohort study. EDS, hypermobility syndrome and psychiatric disorders were identified through Swedish national registries. Individuals with EDS (n = 1,771) were matched with comparison individuals (n = 17,710). Further, siblings to individuals with EDS who did not have an EDS diagnosis themselves were compared with matched comparison siblings. Using conditional logistic regression, risk of autism spectrum disorder (ASD), bipolar disorder, attention deficit hyperactivity disorder (ADHD), depression, attempted suicide, suicide and schizophrenia were estimated. The same analyses were conducted in individuals with hypermobility syndrome (n = 10,019) and their siblings.
Results
EDS was associated with ASD: risk ratio (RR) 7.4, 95 % confidence interval (95 % CI) 5.2–10.7; bipolar disorder: RR 2.7, CI 1.5–4.7; ADHD: RR 5.6, CI 4.2–7.4; depression: RR 3.4, 95 % CI 2.9–4.1; and attempted suicide: RR 2.1, 95 % CI 1.7–2.7, but not with suicide or schizophrenia. EDS siblings were at increased risk of ADHD: RR 2.1, 95 % CI 1.4–3.3; depression: RR 1.5, 95 % CI 1.1–1.8; and suicide attempt: RR 1.8, 95 % CI 1.4–2.3. Similar results were observed for individuals with hypermobility syndrome and their siblings.
Conclusions
Individuals with EDS and hypermobility syndrome are at increased risks of being diagnosed with psychiatric disorders. These risk increases may have a genetic and/or early environmental background as suggested by evidence showing that siblings to patients have elevated risks of certain psychiatric disorders.
Electronic supplementary material
The online version of this article (doi:10.1186/s12888-016-0922-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s12888-016-0922-6
PMCID: PMC4932739  PMID: 27377649
Cohort study; Ehlers-Danlos syndrome; Hypermobility syndrome; Epidemiology; Psychiatric disorders
12.  Genetic and environmental influences on height from infancy to early adulthood: An individual-based pooled analysis of 45 twin cohorts 
Jelenkovic, Aline | Sund, Reijo | Hur, Yoon-Mi | Yokoyama, Yoshie | Hjelmborg, Jacob v. B. | Möller, Sören | Honda, Chika | Magnusson, Patrik K. E. | Pedersen, Nancy L. | Ooki, Syuichi | Aaltonen, Sari | Stazi, Maria A. | Fagnani, Corrado | D’Ippolito, Cristina | Freitas, Duarte L. | Maia, José Antonio | Ji, Fuling | Ning, Feng | Pang, Zengchang | Rebato, Esther | Busjahn, Andreas | Kandler, Christian | Saudino, Kimberly J. | Jang, Kerry L. | Cozen, Wendy | Hwang, Amie E. | Mack, Thomas M. | Gao, Wenjing | Yu, Canqing | Li, Liming | Corley, Robin P. | Huibregtse, Brooke M. | Derom, Catherine A. | Vlietinck, Robert F. | Loos, Ruth J. F. | Heikkilä, Kauko | Wardle, Jane | Llewellyn, Clare H. | Fisher, Abigail | McAdams, Tom A. | Eley, Thalia C. | Gregory, Alice M. | He, Mingguang | Ding, Xiaohu | Bjerregaard-Andersen, Morten | Beck-Nielsen, Henning | Sodemann, Morten | Tarnoki, Adam D. | Tarnoki, David L. | Knafo-Noam, Ariel | Mankuta, David | Abramson, Lior | Burt, S. Alexandra | Klump, Kelly L. | Silberg, Judy L. | Eaves, Lindon J. | Maes, Hermine H. | Krueger, Robert F. | McGue, Matt | Pahlen, Shandell | Gatz, Margaret | Butler, David A. | Bartels, Meike | van Beijsterveldt, Toos C. E. M. | Craig, Jeffrey M. | Saffery, Richard | Dubois, Lise | Boivin, Michel | Brendgen, Mara | Dionne, Ginette | Vitaro, Frank | Martin, Nicholas G. | Medland, Sarah E. | Montgomery, Grant W. | Swan, Gary E. | Krasnow, Ruth | Tynelius, Per | Lichtenstein, Paul | Haworth, Claire M. A. | Plomin, Robert | Bayasgalan, Gombojav | Narandalai, Danshiitsoodol | Harden, K. Paige | Tucker-Drob, Elliot M. | Spector, Timothy | Mangino, Massimo | Lachance, Genevieve | Baker, Laura A. | Tuvblad, Catherine | Duncan, Glen E. | Buchwald, Dedra | Willemsen, Gonneke | Skytthe, Axel | Kyvik, Kirsten O. | Christensen, Kaare | Öncel, Sevgi Y. | Aliev, Fazil | Rasmussen, Finn | Goldberg, Jack H. | Sørensen, Thorkild I. A. | Boomsma, Dorret I. | Kaprio, Jaakko | Silventoinen, Karri
Scientific Reports  2016;6:28496.
Height variation is known to be determined by both genetic and environmental factors, but a systematic description of how their influences differ by sex, age and global regions is lacking. We conducted an individual-based pooled analysis of 45 twin cohorts from 20 countries, including 180,520 paired measurements at ages 1–19 years. The proportion of height variation explained by shared environmental factors was greatest in early childhood, but these effects remained present until early adulthood. Accordingly, the relative genetic contribution increased with age and was greatest in adolescence (up to 0.83 in boys and 0.76 in girls). Comparing geographic-cultural regions (Europe, North-America and Australia, and East-Asia), genetic variance was greatest in North-America and Australia and lowest in East-Asia, but the relative proportion of genetic variation was roughly similar across these regions. Our findings provide further insights into height variation during childhood and adolescence in populations representing different ethnicities and exposed to different environments.
doi:10.1038/srep28496
PMCID: PMC4917845  PMID: 27333805
13.  Schizophrenia, Substance Abuse, and Violent Crime 
JAMA  2009;301(19):2016-2023.
Context
Persons with schizophrenia are thought to be at increased risk of committing violent crime 4 to 6 times the level of general population individuals without this disorder. However, risk estimates vary substantially across studies, and considerable uncertainty exists as to what mediates this elevated risk. Despite this uncertainty, current guidelines recommend that violence risk assessment should be conducted for all patients with schizophrenia.
Objective
To determine the risk of violent crime among patients diagnosed as having schizophrenia and the role of substance abuse in mediating this risk.
Design, Setting, and Participants
Longitudinal designs were used to link data from nationwide Swedish registers of hospital admissions and criminal convictions in 1973-2006. Risk of violent crime in patients after diagnosis of schizophrenia (n = 8003) was compared with that among general population controls (n = 80 025). Potential confounders (age, sex, income, and marital and immigrant status) and mediators (substance abuse comorbidity) were measured at baseline. To study familial confounding, we also investigated risk of violence among unaffected siblings (n = 8123) of patients with schizophrenia. Information on treatment was not available.
Main Outcome Measure
Violent crime (any criminal conviction for homicide, assault, robbery, arson, any sexual offense, illegal threats, or intimidation).
Results
In patients with schizophrenia, 1054 (13.2%) had at least 1 violent offense compared with 4276 (5.3%) of general population controls (adjusted odds ratio [OR], 2.0; 95% confidence interval [CI], 1.8-2.2). The risk was mostly confined to patients with substance abuse comorbidity (of whom 27.6% committed an offense), yielding an increased risk of violent crime among such patients (adjusted OR, 4.4; 95% CI, 3.9-5.0), whereas the risk increase was small in schizophrenia patients without substance abuse comorbidity (8.5% of whom had at least 1 violent offense; adjusted OR, 1.2; 95% CI, 1.1-1.4; P<.001 for interaction). The risk increase among those with substance abuse comorbidity was significantly less pronounced when unaffected siblings were used as controls (28.3% of those with schizophrenia had a violent offense compared with 17.9% of their unaffected siblings; adjusted OR, 1.8; 95% CI, 1.4-2.4; P<.001 for interaction), suggesting significant familial (genetic or early environmental) confounding of the association between schizophrenia and violence.
Conclusions
Schizophrenia was associated with an increased risk of violent crime in this longitudinal study. This association was attenuated by adjustment for substance abuse, suggesting a mediating effect. The role of risk assessment, management, and treatment in individuals with comorbidity needs further examination.
doi:10.1001/jama.2009.675
PMCID: PMC4905518  PMID: 19454640
14.  Prediction of violent reoffending on release from prison: derivation and external validation of a scalable tool 
The lancet. Psychiatry  2016;3(6):535-543.
Background
More than 30 million people are released from prison worldwide every year, who include a group at high risk of perpetrating interpersonal violence. Because there is considerable inconsistency and inefficiency in identifying those who would benefit from interventions to reduce this risk, we developed and validated a clinical prediction rule to determine the risk of violent offending in released prisoners.
Methods
We did a cohort study of a population of released prisoners in Sweden. Through linkage of population-based registers, we developed predictive models for violent reoffending for the cohort. First, we developed a derivation model to determine the strength of prespecified, routinely obtained criminal history, sociodemographic, and clinical risk factors using multivariable Cox proportional hazard regression, and then tested them in an external validation. We measured discrimination and calibration for prediction of our primary outcome of violent reoffending at 1 and 2 years using cutoffs of 10% for 1-year risk and 20% for 2-year risk.
Findings
We identified a cohort of 47 326 prisoners released in Sweden between 2001 and 2009, with 11 263 incidents of violent reoffending during this period. We developed a 14-item derivation model to predict violent reoffending and tested it in an external validation (assigning 37 100 individuals to the derivation sample and 10 226 to the validation sample). The model showed good measures of discrimination (Harrell’s c-index 0.74) and calibration. For risk of violent reoffending at 1 year, sensitivity was 76% (95% CI 73–79) and specificity was 61% (95% CI 60–62). Positive and negative predictive values were 21% (95% CI 19–22) and 95% (95% CI 94–96), respectively. At 2 years, sensitivity was 67% (95% CI 64–69) and specificity was 70% (95% CI 69–72). Positive and negative predictive values were 37% (95% CI 35–39) and 89% (95% CI 88–90), respectively. Of individuals with a predicted risk of violent reoffending of 50% or more, 88% had drug and alcohol use disorders. We used the model to generate a simple, web-based, risk calculator (OxRec) that is free to use.
Interpretation
We have developed a prediction model in a Swedish prison population that can assist with decision making on release by identifying those who are at low risk of future violent offending, and those at high risk of violent reoffending who might benefit from drug and alcohol treatment. Further assessments in other populations and countries are needed.
doi:10.1016/S2215-0366(16)00103-6
PMCID: PMC4898588  PMID: 27086134
15.  Is There a Female Protective Effect Against Attention-Deficit/Hyperactivity Disorder? Evidence From Two Representative Twin Samples 
Objective
Attention-deficit/hyperactivity disorder (ADHD) is more frequent in males than in females. The “female protective effect” posits that females undergo greater exposure to etiological factors than males in order to develop ADHD, leading to the prediction that relatives of females with ADHD will display more ADHD behaviors. We thus tested whether cotwins of females displaying extreme ADHD traits would display more ADHD traits than cotwins of males displaying extreme ADHD traits.
Method
Parents of approximately 7,000 pairs of nonidentical twins in Sweden, and approximately 4,000 pairs of twins in England and Wales, completed dimensional assessments of ADHD traits. Probands were selected on the basis of scoring within the highest 10% of the distribution in each sample. Dimensional scores of cotwins of probands, as well as the categorical recurrence rate, were investigated by proband sex.
Results
Cotwins of female probands displayed higher mean ADHD trait scores (mean = 0.62−0.79) than cotwins of male probands (mean = 0.38−0.55) in both samples. This trend was significant in the Swedish sample (p < .01) and when the 2 samples were merged into a single, larger sample (p < .001). When the samples were merged, there was also a significant association between proband sex and cotwin’s categorical status, with more cotwins of female probands also being probands than cotwins of male probands.
Conclusion
These findings support a female protective effect against ADHD behaviors, suggesting that females require greater exposure to genetic and environmental factors associated with ADHD in order to develop the condition.
doi:10.1016/j.jaac.2016.04.004
PMCID: PMC4896985  PMID: 27238069
ADHD; sex differences; genetics; twin study
16.  A Genetically Informed Study of the Longitudinal Relation Between Irritability and Anxious/Depressed Symptoms 
Objective
Little is known about the longitudinal genetic and environmental association between juvenile irritability and symptoms of anxiety and depression. This study’s goal was to assess the relationship between these constructs across a critical developmental period spanning childhood to young adulthood.
Method
Parents (n=1,348 twin pairs) from the Swedish Twin Study of Child and Adolescent Development completed the Child/Adult Behavior Checklist (CBCL/ABCL) about their twin children. Data were collected during a prospective, four-wave study starting in childhood (ages 8–9) and ending in young adulthood (ages 19–20). An irritability score and an anxious/depressed score were computed from CBCL/ABCL item endorsements. Genetically informative cross-lagged models were used to estimate the genetic and environmental relationship between these two constructs across time.
Results
Our models suggested that irritability more strongly predicted anxious/depressed symptoms than vice versa, consistent with a causal role of irritability on anxiety/depression at older ages. This relationship was significant only in late childhood/early adolescence. Additive genetic and unique environmental factors were significant contributors to both irritability and anxious/depressed symptoms, and were both specific to and shared between these two constructs. The same common environmental factors influenced both constructs, although these factors accounted for a smaller amount of variance than genetic or unique environmental factors.
Conclusion
This study adds to our understanding of the developmental relationship between irritability and anxious/depressed symptoms and the contribution of genes and environmental factors to their association across development. Findings suggest the need to monitor for emergence of internalizing symptoms in irritable children and their potential need for therapeutic intervention.
doi:10.1016/j.jaac.2015.02.010
PMCID: PMC4407138  PMID: 25901774
irritability; anxiety; depression; genetic; twins
17.  Birth weight as an independent predictor of ADHD symptoms: A within-twin pair analysis 
OBJECTIVE
Studies have found an association between low birth weight and ADHD, but the nature of this relation is unclear. First, it is uncertain whether birth weight is associated with both of the ADHD dimensions, inattentiveness and hyperactivity-impulsivity. Second, it remains uncertain whether the association between birth weight and ADHD symptom severity is confounded by familial factors.
METHOD
Parents of all Swedish 9- and 12-year-old twins born between 1992 and 2000 were interviewed for DSM-IV inattentive and hyperactive-impulsive ADHD symptoms by the Autism – Tics, AD/HD and other Comorbidities (A-TAC) inventory (N = 21,775 twins). Birth weight was collected prospectively through the Medical Birth Registry. We used a within-twin pair design to control for genetic and shared environmental factors.
RESULTS
Reduced birth weight was significantly associated with a mean increase in total ADHD (β = −.42; 95% CI: −.53, −.30), inattentive (β = −.26; 95% CI: −.33, −.19), and hyperactive-impulsive (β = −.16; 95% CI: −.22, −.10) symptom severity. These results imply that a change of one kilogram of birth weight corresponded to parents rating their child nearly one unit higher (going from “no” to “yes, to some extent” on a given symptom) on the total ADHD scale. These associations remained within pairs of MZ and DZ twins, and were also present when restricting the analyses to full term births.
CONCLUSIONS
There is an independent association between low birth weight and all forms of ADHD symptoms, even after controlling for all environmental and genetic confounds shared within twin pairs. These results indicate that fetal growth restriction (as reflected in birth weight differences within twin pairs) and/or the environmental factors which influence it is in the casual pathway leading to ADHD.
doi:10.1111/jcpp.12299
PMCID: PMC4295006  PMID: 25040291
ADHD; DSM; birth weight; behavioral genetics; environmental influences
18.  Zygosity Differences in Height and Body Mass Index of Twins From Infancy to Old Age: A Study of the CODATwins Project 
Jelenkovic, Aline | Yokoyama, Yoshie | Sund, Reijo | Honda, Chika | Bogl, Leonie H. | Aaltonen, Sari | Ji, Fuling | Ning, Feng | Pang, Zengchang | Ordoñana, Juan R. | Sánchez-Romera, Juan F. | Colodro-Conde, Lucia | Burt, S. Alexandra | Klump, Kelly L. | Medland, Sarah E. | Montgomery, Grant W. | Kandler, Christian | McAdams, Tom A. | Eley, Thalia C. | Gregory, Alice M. | Saudino, Kimberly J. | Dubois, Lise | Boivin, Michel | Tarnoki, Adam D. | Tarnoki, David L. | Haworth, Claire M. A. | Plomin, Robert | Öncel, Sevgi Y. | Aliev, Fazil | Stazi, Maria A. | Fagnani, Corrado | D’Ippolito, Cristina | Craig, Jeffrey M. | Saffery, Richard | Siribaddana, Sisira H. | Hotopf, Matthew | Sumathipala, Athula | Rijsdijk, Fruhling | Spector, Timothy | Mangino, Massimo | Lachance, Genevieve | Gatz, Margaret | Butler, David A. | Bayasgalan, Gombojav | Narandalai, Danshiitsoodol | Freitas, Duarte L. | Maia, José Antonio | Harden, K. Paige | Tucker-Drob, Elliot M. | Kim, Bia | Chong, Youngsook | Hong, Changhee | Shin, Hyun Jung | Christensen, Kaare | Skytthe, Axel | Kyvik, Kirsten O. | Derom, Catherine A. | Vlietinck, Robert F. | Loos, Ruth J. F. | Cozen, Wendy | Hwang, Amie E. | Mack, Thomas M. | He, Mingguang | Ding, Xiaohu | Chang, Billy | Silberg, Judy L. | Eaves, Lindon J. | Maes, Hermine H. | Cutler, Tessa L. | Hopper, John L. | Aujard, Kelly | Magnusson, Patrik K. E. | Pedersen, Nancy L. | Dahl Aslan, Anna K. | Song, Yun-Mi | Yang, Sarah | Lee, Kayoung | Baker, Laura A. | Tuvblad, Catherine | Bjerregaard-Andersen, Morten | Beck-Nielsen, Henning | Sodemann, Morten | Heikkilä, Kauko | Tan, Qihua | Zhang, Dongfeng | Swan, Gary E. | Krasnow, Ruth | Jang, Kerry L. | Knafo-Noam, Ariel | Mankuta, David | Abramson, Lior | Lichtenstein, Paul | Krueger, Robert F. | McGue, Matt | Pahlen, Shandell | Tynelius, Per | Duncan, Glen E. | Buchwald, Dedra | Corley, Robin P. | Huibregtse, Brooke M. | Nelson, Tracy L. | Whitfield, Keith E. | Franz, Carol E. | Kremen, William S. | Lyons, Michael J. | Ooki, Syuichi | Brandt, Ingunn | Nilsen, Thomas Sevenius | Inui, Fujio | Watanabe, Mikio | Bartels, Meike | van Beijsterveldt, Toos C. E. M. | Wardle, Jane | Llewellyn, Clare H. | Fisher, Abigail | Rebato, Esther | Martin, Nicholas G. | Iwatani, Yoshinori | Hayakawa, Kazuo | Sung, Joohon | Harris, Jennifer R. | Willemsen, Gonneke | Busjahn, Andreas | Goldberg, Jack H. | Rasmussen, Finn | Hur, Yoon-Mi | Boomsma, Dorret I. | Sørensen, Thorkild I. A. | Kaprio, Jaakko | Silventoinen, Karri
A trend toward greater body size in dizygotic (DZ) than in monozygotic (MZ) twins has been suggested by some but not all studies, and this difference may also vary by age. We analyzed zygosity differences in mean values and variances of height and body mass index (BMI) among male and female twins from infancy to old age. Data were derived from an international database of 54 twin cohorts participating in the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins), and included 842,951 height and BMI measurements from twins aged 1 to 102 years. The results showed that DZ twins were consistently taller than MZ twins, with differences of up to 2.0 cm in childhood and adolescence and up to 0.9 cm in adulthood. Similarly, a greater mean BMI of up to 0.3 kg/m2 in childhood and adolescence and up to 0.2 kg/m2 in adulthood was observed in DZ twins, although the pattern was less consistent. DZ twins presented up to 1.7% greater height and 1.9% greater BMI than MZ twins; these percentage differences were largest in middle and late childhood and decreased with age in both sexes. The variance of height was similar in MZ and DZ twins at most ages. In contrast, the variance of BMI was significantly higher in DZ than in MZ twins, particularly in childhood. In conclusion, DZ twins were generally taller and had greater BMI than MZ twins, but the differences decreased with age in both sexes.
doi:10.1017/thg.2015.57
PMCID: PMC4605819  PMID: 26337138
twins; height; BMI; zygosity differences
19.  A population-based Swedish Twin and Sibling Study of cannabis, stimulant and sedative abuse in men 
Drug and alcohol dependence  2015;149:49-54.
Background
Prior studies, utilizing interview-based assessments, suggest that most of the genetic risk factors for drug abuse (DA) are non-specific with a minority acting specifically on risk for abuse of particular psychoactive substance classes. We seek to replicate these findings using objective national registry data.
Methods
We examined abuse of cannabis, stimulants (including cocaine) and sedatives ascertained from national Swedish registers in male–male monozygotic (1720 pairs) and dizygotic twins (1219 pairs) combined with near-age full siblings (76,457 pairs) to provide sufficient power. Modeling was performed using Mx.
Results
A common pathway model fitted better than an independent pathway model. The latent liability to DA was highly heritable but also influenced by shared environment. Cannabis, stimulant and sedative abuse all loaded strongly on the common factor. Estimates for the total heritability for the three forms of substance abuse ranged from 64 to 70%. Between 75 and 90% of that genetic risk was non-specific, coming from the common factor with the remainder deriving from substance specific genetic risk factors. By contrast, all of the shared environmental effects, which accounted for 18–20% of the variance in liability, were non-specific.
Conclusions
In accord with prior studies based on personal interviews, the large preponderance of genetic risk factors for abuse of specific classes of psychoactive substance are non-specific. These results suggest that genetic variation in the primary sites of action of the psychoactive drugs, which differ widely across most drug classes, play a minor role in human individual differences in risk for DA.
doi:10.1016/j.drugalcdep.2015.01.016
PMCID: PMC4431972  PMID: 25660314
Genetics; Drug abuse; Cannabis; Stimulants; Sedatives; Twins
20.  Zygosity differences in height and body mass index of twins from infancy to old age: A study of the CODATwins project 
Jelenkovic, Aline | Yokoyama, Yoshie | Sund, Reijo | Honda, Chika | Bogl, Leonie H | Aaltonen, Sari | Ji, Fuling | Ning, Feng | Pang, Zengchang | Ordoñana, Juan R | Sánchez-Romera, Juan F | Colodro-Conde, Lucia | Burt, S Alexandra | Klump, Kelly L | Medland, Sarah E | Montgomery, Grant W | Kandler, Christian | McAdams, Tom A | Eley, Thalia C | Gregory, Alice M | Saudino, Kimberly J | Dubois, Lise | Boivin, Michel | Tarnoki, Adam D | Tarnoki, David L | Haworth, Claire MA | Plomin, Robert | Öncel, Sevgi Y | Aliev, Fazil | Stazi, Maria A | Fagnani, Corrado | D'Ippolito, Cristina | Craig, Jeffrey M | Saffery, Richard | Siribaddana, Sisira H | Hotopf, Matthew | Sumathipala, Athula | Rijsdijk, Fruhling | Spector, Timothy | Mangino, Massimo | Lachance, Genevieve | Gatz, Margaret | Butler, David A | Bayasgalan, Gombojav | Narandalai, Danshiitsoodol | Freitas, Duarte L | Maia, José Antonio | Harden, K Paige | Tucker-Drob, Elliot M | Kim, Bia | Chong, Youngsook | Hong, Changhee | Shin, Hyun Jung | Christensen, Kaare | Skytthe, Axel | Kyvik, Kirsten O | Derom, Catherine A | Vlietinck, Robert F | Loos, Ruth JF | Cozen, Wendy | Hwang, Amie E | Mack, Thomas M | He, Mingguang | Ding, Xiaohu | Chang, Billy | Silberg, Judy L | Eaves, Lindon J | Maes, Hermine H | Cutler, Tessa L | Hopper, John L | Aujard, Kelly | Magnusson, Patrik KE | Pedersen, Nancy L | Aslan, Anna K Dahl | Song, Yun-Mi | Yang, Sarah | Lee, Kayoung | Baker, Laura A | Tuvblad, Catherine | Bjerregaard-Andersen, Morten | Beck-Nielsen, Henning | Sodemann, Morten | Heikkilä, Kauko | Tan, Qihua | Zhang, Dongfeng | Swan, Gary E | Krasnow, Ruth | Jang, Kerry L | Knafo-Noam, Ariel | Mankuta, David | Abramson, Lior | Lichtenstein, Paul | Krueger, Robert F | McGue, Matt | Pahlen, Shandell | Tynelius, Per | Duncan, Glen E | Buchwald, Dedra | Corley, Robin P | Huibregtse, Brooke M | Nelson, Tracy L | Whitfield, Keith E | Franz, Carol E | Kremen, William S | Lyons, Michael J | Ooki, Syuichi | Brandt, Ingunn | Nilsen, Thomas Sevenius | Inui, Fujio | Watanabe, Mikio | Bartels, Meike | van Beijsterveldt, Toos CEM | Wardle, Jane | Llewellyn, Clare H | Fisher, Abigail | Rebato, Esther | Martin, Nicholas G | Iwatani, Yoshinori | Hayakawa, Kazuo | Sung, Joohon | Harris, Jennifer R | Willemsen, Gonneke | Busjahn, Andreas | Goldberg, Jack H | Rasmussen, Finn | Hur, Yoon-Mi | Boomsma, Dorret I | Sørensen, Thorkild IA | Kaprio, Jaakko | Silventoinen, Karri
A trend towards greater body size in dizygotic (DZ) than in monozygotic (MZ) twins has been suggested by some but not all studies, and this difference may also vary by age. We analyzed zygosity differences in means and variances of height and body mass index (BMI) among male and female twins from infancy to old age. Data were derived from an international database of 54 twin cohorts participating in the CODATwins project and included 842,951 height and BMI measurements from age 1 to 102 years. The results showed that DZ twins were consistently taller than MZ twins, with differences of up to 2.0 cm in childhood and adolescence and up to 0.9 cm in adulthood. Likewise, a greater mean BMI of up to 0.3 kg/m2 in childhood and adolescence and up to 0.2 kg/m2 in adulthood was observed in DZ twins, although the pattern was less consistent. DZ twins presented up to 1.7% greater height and 1.9% greater BMI than MZ twins; these percentage differences were largest in middle and late childhood and decreased with age in both sexes. The variance of height was similar in MZ and DZ twins at most ages. In contrast the variance of BMI was significantly higher in DZ than in MZ twins particularly in childhood. In conclusion, DZ twins were generally taller and had greater BMI than MZ twins, but the differences decreased with age in both sexes.
doi:10.1017/thg.2015.57
PMCID: PMC4605819  PMID: 26337138
21.  Does Population Density and Neighborhood Deprivation Predict Schizophrenia? A Nationwide Swedish Family-Based Study of 2.4 Million Individuals 
Schizophrenia Bulletin  2014;41(2):494-502.
People living in densely populated and socially disorganized areas have higher rates of psychiatric morbidity, but the potential causal status of such factors is uncertain. We used nationwide Swedish longitudinal registry data to identify all children born 1967–1989 (n = 2361585), including separate datasets for all cousins (n = 1715059) and siblings (n = 1667894). The nature of the associations between population density and neighborhood deprivation and individual risk for a schizophrenia diagnosis was investigated while adjusting for unobserved familial risk factors (through cousin and sibling comparisons) and then compared with similar associations for depression. We generated familial pedigree structures using the Multi-Generation Registry and identified study participants with schizophrenia and depression using the National Patient Registry. Fixed-effects logistic regression models were used to study within-family estimates. Population density, measured as ln(population size/km2), at age 15 predicted subsequent schizophrenia in the population (OR = 1.10; 95% CI: 1.09; 1.11). Unobserved familial risk factors shared by cousins within extended families attenuated the association (1.06; 1.03; 1.10), and the link disappeared entirely within nuclear families (1.02; 0.97; 1.08). Similar results were found for neighborhood deprivation as predictor and for depression as outcome. Sensitivity tests demonstrated that timing and accumulation effects of the exposures (mean scores across birth, ages 1–5, 6–10, and 11–15 years) did not alter the findings. Excess risks of psychiatric morbidity, particularly schizophrenia, in densely populated and socioeconomically deprived Swedish neighborhoods appear, therefore, to result primarily from unobserved familial selection factors. Previous studies may have overemphasized the etiological importance of these environmental factors.
doi:10.1093/schbul/sbu105
PMCID: PMC4332947  PMID: 25053652
schizophrenia; urbanization; socioeconomic factors; multilevel models; confounding factors; quasiexperimental designs
22.  Risks of Psychiatric Disorders and Suicide Attempts in Children and Adolescents With Type 1 Diabetes: A Population-Based Cohort Study 
Diabetes Care  2015;38(3):453-459.
OBJECTIVE
To assess the risk of psychiatric disorders and suicide attempts in children with type 1 diabetes and their healthy siblings.
RESEARCH DESIGN AND METHODS
We performed a population-based case-cohort study of individuals born in Sweden between 1973 and 2009. Children with type 1 diabetes (n = 17,122) and their healthy siblings (n = 18,847) were identified and followed until their 18th birthday. Their risk of psychiatric disorders was compared with that of matched control subjects.
RESULTS
The risk of psychiatric morbidity in children with type 1 diabetes compared with the general population was tripled within 6 months after the onset of diabetes (hazard ratio [HR] 3.0 [95% CI 2.7–3.4]) and doubled within the total observation period (HR 2.1 [95% CI 2.0–2.2]). An increased risk was noted in suicide attempts (HR 1.7 [95% CI 1.4–2.0]) and in most categories of psychiatric disorders. The risk of psychiatric disorders in probands declined from HR 2.7 (95% CI 2.2–3.3) for those in the cohort born 1973–1986 to 1.9 (95% CI 1.8–2.0) in those born 1997–2009. The risk for any psychiatric disorders among siblings of patients with type 1 diabetes was estimated to be HR 1.1 (95% CI 1.0–1.1), and there was no increased risk in any of the specific category of disorders.
CONCLUSIONS
Children with type 1 diabetes are at high risk of psychiatric disorders, which seems to be a consequence of the disease rather than due to a common familial etiology. The results support recommendations on comprehensive mental health surveillance in children with type 1 diabetes, especially in recently diagnosed children.
doi:10.2337/dc14-0262
PMCID: PMC4338504  PMID: 25650362
23.  Application of linear mixed models to study genetic stability of height and body mass index across countries and time 
Background: It is now possible to estimate genetic correlations between two independent samples when there is no overlapping phenotypic information. We applied the latest bivariate genomic methods to children in the UK and older adults in Sweden to ask two questions. Are the same variants driving individual differences in anthropometric traits in these two populations, and are these variants as important in childhood as they are later in life?
Methods: A sample of 3152 11-year-old children in the UK was compared with a sample of 6813 adults with an average age of 65 in Sweden. Genotypes were imputed from 1000 genomes with combined 9 767 136 single nucleotide polymorphisms meeting quality control criteria in both samples. Two cross-sample GCTA-GREML analyses and linkage disequilibrium (LD) score regressions were conducted to assess genetic correlations across more than 50 years: child versus adult height and child versus adult body mass index (BMI). Consistency of effects was tested using the recently proposed polygenic scoring method.
Results: For height, GCTA-GREML and LD score indicated strong genetic stability between children and adults, 0.58 (0.16) and 1.335 (1.09), respectively. For BMI, both methods produced similarly strong estimates of genetic stability 0.75 (0.26) and 0.855 (0.49), respectively. In height, adult polygenic score explained 60% of genetic variance in childhood and 10% of variance in BMI.
Conclusions: Here we replicated and extended previous findings of longitudinal genetic stability in anthropometric traits to cross-cultural dimensions, and showed that for height but not BMI these variants are as important in childhood as they are in adulthood.
doi:10.1093/ije/dyv355
PMCID: PMC4864877  PMID: 26819444
Unrelated samples; GCTA; GREML; genetic stability; height; weight; BMI; LD score regression; polygenic prediction
24.  Effect of co-twin gender on neurodevelopmental symptoms: a twin register study 
Molecular Autism  2016;7:8.
Background
Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are neurodevelopmental disorders thought to have both genetic and environmental causes. It has been hypothesized that exposure to elevated levels of prenatal testosterone is associated with elevated traits of ASD and ADHD. Assuming that testosterone levels from a dizygotic male twin fetus may lead to enhanced testosterone exposure of its co-twins, we aimed to test the prenatal testosterone hypothesis by comparing same-sex with opposite-sex dizygotic twins with respect to neurodevelopmental symptoms.
Methods
Neuropsychiatric traits were assessed in a population-based twin cohort from the Child and Adolescent Twin Study in Sweden (CATSS). Parental interviews were conducted for 16,312 dizygotic twins, 9 and 12 years old, with the Autism—Tics, ADHD, and other Comorbidities inventory (A-TAC).
Results
Girls with a female co-twin had an increased risk of reaching the cut-off score for ADHD compared with girls with a male co-twin. Both boys and girls with a female co-twin displayed a larger number of traits related to attention deficit and repetitive and stereotyped behaviors than those with a male twin. In girls, this also extended to social interaction and the combined measures for ASD and ADHD, however, with small effect sizes.
Conclusions
Our results are reverse to what would have been expected from the prenatal testosterone hypothesis but consistent with a previous study of ASD and ADHD traits in dizygotic twins. The seemingly protective effect for girls of having a twin brother may be an effect of parent report bias, but may also be an unexpected effect of sharing the intrauterine environment with a male co-twin.
doi:10.1186/s13229-016-0074-z
PMCID: PMC4719693  PMID: 26793297
Twin study; Autistic disorder; Asperger syndrome; Attention-deficit hyperactivity disorders; Symptom assessment
25.  Air Pollution Exposure during Pregnancy and Childhood Autistic Traits in Four European Population-Based Cohort Studies: The ESCAPE Project 
Environmental Health Perspectives  2015;124(1):133-140.
Background
Prenatal exposure to air pollutants has been suggested as a possible etiologic factor for the occurrence of autism spectrum disorder.
Objectives
We aimed to assess whether prenatal air pollution exposure is associated with childhood autistic traits in the general population.
Methods
Ours was a collaborative study of four European population-based birth/child cohorts—CATSS (Sweden), Generation R (the Netherlands), GASPII (Italy), and INMA (Spain). Nitrogen oxides (NO2, NOx) and particulate matter (PM) with diameters of ≤ 2.5 μm (PM2.5), ≤ 10 μm (PM10), and between 2.5 and 10 μm (PMcoarse), and PM2.5 absorbance were estimated for birth addresses by land-use regression models based on monitoring campaigns performed between 2008 and 2011. Levels were extrapolated back in time to exact pregnancy periods. We quantitatively assessed autistic traits when the child was between 4 and 10 years of age. Children were classified with autistic traits within the borderline/clinical range and within the clinical range using validated cut-offs. Adjusted cohort-specific effect estimates were combined using random-effects meta-analysis.
Results
A total of 8,079 children were included. Prenatal air pollution exposure was not associated with autistic traits within the borderline/clinical range (odds ratio = 0.94; 95% CI: 0.81, 1.10 per each 10-μg/m3 increase in NO2 pregnancy levels). Similar results were observed in the different cohorts, for the other pollutants, and in assessments of children with autistic traits within the clinical range or children with autistic traits as a quantitative score.
Conclusions
Prenatal exposure to NO2 and PM was not associated with autistic traits in children from 4 to 10 years of age in four European population-based birth/child cohort studies.
Citation
Guxens M, Ghassabian A, Gong T, Garcia-Esteban R, Porta D, Giorgis-Allemand L, Almqvist C, Aranbarri A, Beelen R, Badaloni C, Cesaroni G, de Nazelle A, Estarlich M, Forastiere F, Forns J, Gehring U, Ibarluzea J, Jaddoe VW, Korek M, Lichtenstein P, Nieuwenhuijsen MJ, Rebagliato M, Slama R, Tiemeier H, Verhulst FC, Volk HE, Pershagen G, Brunekreef B, Sunyer J. 2016. Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies: the ESCAPE Project. Environ Health Perspect 124:133–140; http://dx.doi.org/10.1289/ehp.1408483
doi:10.1289/ehp.1408483
PMCID: PMC4710593  PMID: 26068947

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