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1.  Socioeconomic status and sick leave granted for mental and somatic disorders: a prospective study of young adult twins  
BMC Public Health  2015;15:134.
Background
Low socioeconomic status (SES), indicated by low income and education, has consistently been found to be a strong predictor of sick leave. Several possible pathways from SES to sick leave have been described in previous literature, but there are also evidence indicating that the association can be confounded by common underlying factors. This study utilizes a population-based sample of employed young adult twins to estimate (i) the degree to which education and income are prospectively related to sick leave granted for mental, somatic, and any disorder, and (ii) whether these associations are confounded by familial factors.
Methods
Registry data on educational attainment and income at age 30 and subsequent sick leave were available for 6,103 employed young adult twins, among which there were 2,024 complete twin pairs. The average follow-up time was 6.57 years. Individual-level associations and fixed effects within twin pairs were estimated.
Results
Low education and income were associated with sick leave granted for both mental and somatic disorders, and with sick leave granted for any disorder. Associations were attenuated within dizygotic twin pairs and reduced to non-significance within monozygotic twin pairs, suggesting influence of familial factors on the associations between SES and sick leave.
Conclusions
Low SES is associated with a higher level of sick leave granted for both mental and somatic disorders among young adults, but these associations are confounded by factors that are common to co-twins. Education and income are therefore not likely to strongly affect sick leave in young adulthood.
doi:10.1186/s12889-015-1457-3
PMCID: PMC4328925
Sick leave; Education; Income; Health inequalities; Twin study; Norway
2.  Biological Insights From 108 Schizophrenia-Associated Genetic Loci 
Ripke, Stephan | Neale, Benjamin M | Corvin, Aiden | Walters, James TR | Farh, Kai-How | Holmans, Peter A | Lee, Phil | Bulik-Sullivan, Brendan | Collier, David A | Huang, Hailiang | Pers, Tune H | Agartz, Ingrid | Agerbo, Esben | Albus, Margot | Alexander, Madeline | Amin, Farooq | Bacanu, Silviu A | Begemann, Martin | Belliveau, Richard A | Bene, Judit | Bergen, Sarah E | Bevilacqua, Elizabeth | Bigdeli, Tim B | Black, Donald W | Bruggeman, Richard | Buccola, Nancy G | Buckner, Randy L | Byerley, William | Cahn, Wiepke | Cai, Guiqing | Campion, Dominique | Cantor, Rita M | Carr, Vaughan J | Carrera, Noa | Catts, Stanley V | Chambert, Kimberley D | Chan, Raymond CK | Chan, Ronald YL | Chen, Eric YH | Cheng, Wei | Cheung, Eric FC | Chong, Siow Ann | Cloninger, C Robert | Cohen, David | Cohen, Nadine | Cormican, Paul | Craddock, Nick | Crowley, James J | Curtis, David | Davidson, Michael | Davis, Kenneth L | Degenhardt, Franziska | Del Favero, Jurgen | Demontis, Ditte | Dikeos, Dimitris | Dinan, Timothy | Djurovic, Srdjan | Donohoe, Gary | Drapeau, Elodie | Duan, Jubao | Dudbridge, Frank | Durmishi, Naser | Eichhammer, Peter | Eriksson, Johan | Escott-Price, Valentina | Essioux, Laurent | Fanous, Ayman H | Farrell, Martilias S | Frank, Josef | Franke, Lude | Freedman, Robert | Freimer, Nelson B | Friedl, Marion | Friedman, Joseph I | Fromer, Menachem | Genovese, Giulio | Georgieva, Lyudmila | Giegling, Ina | Giusti-Rodríguez, Paola | Godard, Stephanie | Goldstein, Jacqueline I | Golimbet, Vera | Gopal, Srihari | Gratten, Jacob | de Haan, Lieuwe | Hammer, Christian | Hamshere, Marian L | Hansen, Mark | Hansen, Thomas | Haroutunian, Vahram | Hartmann, Annette M | Henskens, Frans A | Herms, Stefan | Hirschhorn, Joel N | Hoffmann, Per | Hofman, Andrea | Hollegaard, Mads V | Hougaard, David M | Ikeda, Masashi | Joa, Inge | Julià, Antonio | Kahn, René S | Kalaydjieva, Luba | Karachanak-Yankova, Sena | Karjalainen, Juha | Kavanagh, David | Keller, Matthew C | Kennedy, James L | Khrunin, Andrey | Kim, Yunjung | Klovins, Janis | Knowles, James A | Konte, Bettina | Kucinskas, Vaidutis | Kucinskiene, Zita Ausrele | Kuzelova-Ptackova, Hana | Kähler, Anna K | Laurent, Claudine | Lee, Jimmy | Lee, S Hong | Legge, Sophie E | Lerer, Bernard | Li, Miaoxin | Li, Tao | Liang, Kung-Yee | Lieberman, Jeffrey | Limborska, Svetlana | Loughland, Carmel M | Lubinski, Jan | Lönnqvist, Jouko | Macek, Milan | Magnusson, Patrik KE | Maher, Brion S | Maier, Wolfgang | Mallet, Jacques | Marsal, Sara | Mattheisen, Manuel | Mattingsdal, Morten | McCarley, Robert W | McDonald, Colm | McIntosh, Andrew M | Meier, Sandra | Meijer, Carin J | Melegh, Bela | Melle, Ingrid | Mesholam-Gately, Raquelle I | Metspalu, Andres | Michie, Patricia T | Milani, Lili | Milanova, Vihra | Mokrab, Younes | Morris, Derek W | Mors, Ole | Murphy, Kieran C | Murray, Robin M | Myin-Germeys, Inez | Müller-Myhsok, Bertram | Nelis, Mari | Nenadic, Igor | Nertney, Deborah A | Nestadt, Gerald | Nicodemus, Kristin K | Nikitina-Zake, Liene | Nisenbaum, Laura | Nordin, Annelie | O’Callaghan, Eadbhard | O’Dushlaine, Colm | O’Neill, F Anthony | Oh, Sang-Yun | Olincy, Ann | Olsen, Line | Van Os, Jim | Pantelis, Christos | Papadimitriou, George N | Papiol, Sergi | Parkhomenko, Elena | Pato, Michele T | Paunio, Tiina | Pejovic-Milovancevic, Milica | Perkins, Diana O | Pietiläinen, Olli | Pimm, Jonathan | Pocklington, Andrew J | Powell, John | Price, Alkes | Pulver, Ann E | Purcell, Shaun M | Quested, Digby | Rasmussen, Henrik B | Reichenberg, Abraham | Reimers, Mark A | Richards, Alexander L | Roffman, Joshua L | Roussos, Panos | Ruderfer, Douglas M | Salomaa, Veikko | Sanders, Alan R | Schall, Ulrich | Schubert, Christian R | Schulze, Thomas G | Schwab, Sibylle G | Scolnick, Edward M | Scott, Rodney J | Seidman, Larry J | Shi, Jianxin | Sigurdsson, Engilbert | Silagadze, Teimuraz | Silverman, Jeremy M | Sim, Kang | Slominsky, Petr | Smoller, Jordan W | So, Hon-Cheong | Spencer, Chris C A | Stahl, Eli A | Stefansson, Hreinn | Steinberg, Stacy | Stogmann, Elisabeth | Straub, Richard E | Strengman, Eric | Strohmaier, Jana | Stroup, T Scott | Subramaniam, Mythily | Suvisaari, Jaana | Svrakic, Dragan M | Szatkiewicz, Jin P | Söderman, Erik | Thirumalai, Srinivas | Toncheva, Draga | Tosato, Sarah | Veijola, Juha | Waddington, John | Walsh, Dermot | Wang, Dai | Wang, Qiang | Webb, Bradley T | Weiser, Mark | Wildenauer, Dieter B | Williams, Nigel M | Williams, Stephanie | Witt, Stephanie H | Wolen, Aaron R | Wong, Emily HM | Wormley, Brandon K | Xi, Hualin Simon | Zai, Clement C | Zheng, Xuebin | Zimprich, Fritz | Wray, Naomi R | Stefansson, Kari | Visscher, Peter M | Adolfsson, Rolf | Andreassen, Ole A | Blackwood, Douglas HR | Bramon, Elvira | Buxbaum, Joseph D | Børglum, Anders D | Cichon, Sven | Darvasi, Ariel | Domenici, Enrico | Ehrenreich, Hannelore | Esko, Tõnu | Gejman, Pablo V | Gill, Michael | Gurling, Hugh | Hultman, Christina M | Iwata, Nakao | Jablensky, Assen V | Jönsson, Erik G | Kendler, Kenneth S | Kirov, George | Knight, Jo | Lencz, Todd | Levinson, Douglas F | Li, Qingqin S | Liu, Jianjun | Malhotra, Anil K | McCarroll, Steven A | McQuillin, Andrew | Moran, Jennifer L | Mortensen, Preben B | Mowry, Bryan J | Nöthen, Markus M | Ophoff, Roel A | Owen, Michael J | Palotie, Aarno | Pato, Carlos N | Petryshen, Tracey L | Posthuma, Danielle | Rietschel, Marcella | Riley, Brien P | Rujescu, Dan | Sham, Pak C | Sklar, Pamela | St Clair, David | Weinberger, Daniel R | Wendland, Jens R | Werge, Thomas | Daly, Mark J | Sullivan, Patrick F | O’Donovan, Michael C
Nature  2014;511(7510):421-427.
Summary
Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here, we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain providing biological plausibility for the findings. Many findings have the potential to provide entirely novel insights into aetiology, but associations at DRD2 and multiple genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that play important roles in immunity, providing support for the hypothesized link between the immune system and schizophrenia.
doi:10.1038/nature13595
PMCID: PMC4112379  PMID: 25056061
3.  Age, period and cohort trends in drug abuse hospitalizations within the total Swedish population (1975-2010)* 
Drug and alcohol dependence  2013;134:355-361.
Background:
The societal consequences of drug abuse (DA) are severe and well documented, the World Health Organization recommending tracking of population trends for effective policy responses in treatment of DA and delivery of health care services. However, to correctly identify possible sources of DA change, one must first disentangle three different time-related influences on the need for treatment due to DA: age effects, period effects and cohort effects.
Methods:
We constructed our main Swedish national DA database (spanning four decades) by linking healthcare data from the Swedish Hospital Discharge Register to individuals, which included hospitalisations in Sweden for 1975-2010. All hospitalized DA cases were identified by ICD codes. Our Swedish national sample consisted of 3,078,129 men and 2,921,816 women. We employed a cross-classified multilevel logistic regression model to disentangle any net age, period and cohort effects on DA hospitalization rates.
Results:
We found distinct net age, period and cohort effects, each influencing the predicted probability ofhospitalisation for DA in men and women. Peak age for DA in both sexes was 33-35 years; net period effects showed an increase in hospitalisation for DA from 1996 to 2001; and in birth cohorts 1968-74, we saw a considerable reduction (around 75%) in predicted probability of hospitalisation for DA.
Conclusions:
The use of hospital admissions could be regarded as a proxy of the population's health service use for DA. Our results may thus constitute a basis for effective prevention planning, treatment and other appropriate policy responses.
doi:10.1016/j.drugalcdep.2013.11.011
PMCID: PMC3909834  PMID: 24300899
Sweden; drug abuse; age-period-cohort effects; longitudinal; trends
4.  Molecular Validation of the Schizophrenia Spectrum 
Schizophrenia Bulletin  2013;40(1):60-65.
Background: Early descriptive work and controlled family and adoption studies support the hypothesis that a range of personality and nonschizophrenic psychotic disorders aggregate in families of schizophrenic probands. Can we validate, using molecular polygene scores from genome-wide association studies (GWAS), this schizophrenia spectrum? Methods: The predictive value of polygenic findings reported by the Psychiatric GWAS Consortium (PGC) was applied to 4 groups of relatives from the Irish Study of High-Density Schizophrenia Families (ISHDSF; N = 836) differing on their assignment within the schizophrenia spectrum. Genome-wide single nucleotide polymorphism data for affected and unaffected relatives were used to construct per-individual polygene risk scores based on the PGC stage-I results. We compared mean polygene scores in the ISHDSF with mean scores in ethnically matched population controls (N = 929). Results: The schizophrenia polygene score differed significantly across diagnostic categories and was highest in those with narrow schizophrenia spectrum, lowest in those with no psychiatric illness, and in-between in those classified in the intermediate, broad, and very broad schizophrenia spectrum. Relatives of all of these groups of affected subjects, including those with no diagnosis, had schizophrenia polygene scores significantly higher than the control sample. Conclusions: In the relatives of high-density families, the observed pattern of enrichment of molecular indices of schizophrenia risk suggests an underlying, continuous liability distribution and validates, using aggregate common risk alleles, a genetic basis for the schizophrenia spectrum disorders. In addition, as predicted by genetic theory, nonpsychotic members of multiply-affected schizophrenia families are significantly enriched for replicated, polygenic risk variants compared with the general population.
doi:10.1093/schbul/sbt122
PMCID: PMC3885304  PMID: 23970557
schizophrenia; schizophrenia spectrum; polygene score; GWAS
5.  Genetic and Environmental Risk Factors for Illicit Substance Use and Use Disorders: Joint Analysis of Self and Co-twin Ratings 
Behavior genetics  2013;44(1):1-13.
The specificity of genetic and environmental risk factors for illicit substance use and substance use disorders (SUD) was investigated by utilizing self and co-twin reports in 1,791 male twins. There was a high rate of comorbidity between both use of, and SUD from, different classes of illicit substances. For substance use, the model that included one common genetic, one shared environmental, and one individual-specific (i.e., unique) environmental factor, along with substance-specific effects that were attributed entirely to genetic factors fit the data best. For illicit SUD, one common genetic and one common unique environmental risk factor, and substance specific shared environmental and unique environmental risk factors were identified. Risk factors for illicit substance use and SUD are mainly non-specific to substance class. Co-twin rating of illicit substance use and SUD was a reliable source of information, and by taking account of random and systematic measurement error, environmental exposures unique to the individual were of lesser importance than found in earlier studies.
doi:10.1007/s10519-013-9626-6
PMCID: PMC3893354  PMID: 24196977
Illicit drugs; Substance use; Substance abuse; Comorbidity; Rater bias; Co-twin report
6.  Trauma Exposure and Axis I Psychopathology: A Co-twin Control Analysis in Norwegian Young Adults 
Broad associations between trauma exposure (TE) and Axis I psychopathology have been noted in the literature. However, it is not clear if TE is directly associated with Axis I disorders or if the relationship is better accounted for by familial factors (i.e., early environment and/or genetic factors). The current investigation used the co-twin control method in a large sample of adult twin pairs from the Norwegian Twin Registry (N = 2,776), including 449 twin pairs discordant for DSM-IV Criterion A TE. History of TE and Axis I psychopathology was assessed using DSM-IV based clinical interview. Results suggested that TE was significantly associated with greater likelihood of meeting criteria for major depression, dysthymia, anxiety, substance abuse, eating disorders, and somatization disorder in the general population (odds ratios [OR] ranging from 1.33 to 2.21). Among twins discordant for TE, results suggested that TE may exert a direct influence on major depression, dysthymia, anxiety, substance abuse, eating disorders, and somatization disorder. Shared familial effects may also account for at least some of the relationship between TE and major depression. TE may play an important role in the development of a wide range of Axis I psychopathology above and beyond familial factors. Research and clinical implications are discussed.
doi:10.1037/a0034326
PMCID: PMC4276315  PMID: 25544868
lifetime trauma exposure; co-twin control design; psychopathology; psychiatric genetics
7.  Dimensions of Parental Alcohol Use/Problems and Offspring Temperament, Externalizing Behaviors and Alcohol Use/Problems 
Alcoholism, clinical and experimental research  2013;37(12):10.1111/acer.12196.
BACKGROUND
Alcohol consumption (AC) and alcohol-related problems (AP) are complex traits. How many factors reflecting parental AC and AP are present in the large prospectively followed Avon Longitudinal Study of Parents and Children cohort? Would these factors be uniquely associated with various temperamental and alcohol related outcomes in the children?
METHODS
We factor analyzed multiple items reflecting maternal and paternal AC and AP measured over a 12 year period from before the birth of the child (n=14,093 families). We examined, by linear regression controlling for socio-economic status SES, the relationship between scales derived from these factors and offspring early childhood temperament, externalizing traits and adolescent AC and AP (n’s ranging from 9,732 to 3,454).
RESULTS
We identified 5 coherent factors: typical maternal AC, maternal AC during pregnancy, maternal AP, paternal AC, and paternal AP. In univariate analyses, maternal and paternal AC and AP were modestly and significantly associated with low shyness, sociability, hyperactivity, and conduct problems in childhood and early adolescence; delinquent behavior at age 15; and AC and AP at ages 15 and 18. AC and AP at age 18 were more strongly predicted by parental factors than at age 15. Maternal AC during pregnancy uniquely predicted externalizing traits at ages 4, 13 and 15.
CONCLUSION
Parental AC and AP are complex multidimensional traits that differ in their association with a range of relevant measures in their children. Controlling for background AC and AP, self-reported levels of maternal AC during pregnancy uniquely predicted externalizing behaviors in childhood and adolescence.
doi:10.1111/acer.12196
PMCID: PMC3855174  PMID: 23895510
ALSPAC; alcohol consumption; parental alcohol use; temperament; externalizing problems; fetal alcohol exposure
8.  Depression, anxiety, and prevalent diabetes in the Chinese population: Findings from the China Kadoorie Biobank of 0.5 million people 
Journal of psychosomatic research  2013;75(6):511-517.
Objective
Despite previous investigation, uncertainty remains about the nature of the associations of major depression (MD) with type 2 diabetes mellitus (T2DM), particularly in adult Chinese, and the relevance of generalized anxiety disorder (GAD) for T2DM.
Methods
Cross-sectional data from the China Kadoorie Biobank Study, a sample of approximately 500,000 adults from 10 geographically defined regions of China, were analyzed. Past year MD and GAD were assessed using the Composite International Diagnostic Inventory. T2DM was defined as either having self-reported physician diagnosis of diabetes at age 30 or later (“clinically-identified” cases) or having a non-fasting blood glucose ≥11.1 mmol/L or fasting blood glucose ≥7.0 mmol/L but no prior diagnosis of diabetes (“screen-detected” cases). Logistic regression was used to assess the relationship between MD and GAD with clinically-identified and screen-detected T2DM, adjusting for demographic characteristics and health behaviors.
Results
The prevalence of T2DM was 5.3% (3.2% clinically-identified and 2.1% screen-detected). MD was significantly associated with clinically-identified T2DM (Odds ratio [OR]: 1.75, 95% Confidence Interval (CI): 1.47 – 2.08), but not with screen-detected T2DM (OR: 1.18, 95% CI: 0.92 – 1.51). GAD was associated with both clinically-identified (OR: 2.14, 95% CI: 1.60 – 2.88) and screen-detected (OR: 1.44, 95% CI: 0.99 – 2.08) T2DM. The relationship between MD and GAD with T2DM was moderated by obesity.
Conclusion
MD is associated with clinically-identified, but not screen-detected T2DM. GAD is associated with both clinically-identified and screen-detected T2DM. The relationship between MD and T2DM is strongest among those who are not obese.
doi:10.1016/j.jpsychores.2013.09.008
PMCID: PMC3919064  PMID: 24290039
anxiety; culture; depression; epidemiology; type 2 diabetes
9.  The genetic overlap between schizophrenia and height 
Schizophrenia research  2013;151(0):226-228.
Epidemiological studies suggest that height and schizophrenia risk are inversely correlated. These findings might arise because i) height and schizophrenia share genetic variants and ii) the effects of these shared variants are in opposite direction for the two traits. We use genome wide association data to empirically evaluate these hypotheses. We find that variants which impact on height and risk for schizophrenia are distributed across several genomic regions and the directions of effect vary, some consistent and others inconsistent with the direction expected from the phenotypic data. Moreover, signals that were in and not in accord with the phenotypic data aggregated in distinct biological pathways.
doi:10.1016/j.schres.2013.10.016
PMCID: PMC3939673  PMID: 24239283
Shrinkage; Suggestive signals; Network analysis
10.  Creating a Social World 
Archives of general psychiatry  2007;64(8):958-965.
Context
Peer-group deviance is strongly associated with externalizing behaviors. We have limited knowledge of the sources of individual differences in peer-group deviance.
Objective
To clarify genetic and environmental contributions to peer-group deviance in twins from mid-childhood through early adulthood.
Design
Retrospective assessments using a life-history calendar. Analysis by biometric growth curves.
Setting
General community.
Participants
Members of male-male pairs from the population-based Virginia Twin Registry personally interviewed in 1998–2004 (n=1802).
Main Outcome Measure
Self-reported peer-group deviance at ages 8 to 11, 12 to 14, 15 to 17, 18 to 21, and 22 to 25 years.
Results
Mean and variance of peer-group deviance increased substantially with age. Genetic effects on peer-group deviance showed a strong and steady increase over time. Family environment generally declined in importance over time. Individual-specific environmental influences on peer-group deviance levels were stable in the first 3 age periods and then increased as most twins left home. When standardized, the heritability of peer-group deviance is approximately 30% at ages 8 to 11 years and rises to approximately 50% across the last 3 time periods. Both genes and shared environment contributed to individual differences in the developmental trajectory of peer-group deviance. However, while the correlation between childhood peer-group deviance levels and the subsequent slope of peer-group deviance over time resulting from genetic factors was positive, the same relationship resulting from shared environmental factors was negative.
Conclusions
As male twins mature and create their own social worlds, genetic factors play an increasingly important role in their choice of peers, while shared environment becomes less influential. The individual specific environment increases in importance when individuals leave home. Individuals who have deviant peers in childhood, as a result of genetic vs shared environmental influences, have distinct developmental trajectories. Understanding the risk factors for peer-group deviance will help clarify the etiology of a range of externalizing psychopathology.
doi:10.1001/archpsyc.64.8.958
PMCID: PMC4246499  PMID: 17679640
11.  Parenting and risk for mood, anxiety and substance use disorders: a study in population-based male twins 
Background
Previous studies consistently identified a relationship between parenting behavior and psychopathology. In this study, we extended prior analyses performed in female twins to a large sample of twins from male–male pairs.
Methods
We used interview data on 2,609 adult male twins from a population-based twin registry. We examined the association between three retrospectively reported parenting dimensions (coldness, protectiveness, and authoritarianism) and lifetime history of seven common psychiatric and substance use disorders. Using univariate structural equation modeling, we also examined the influence of the genetic and environmental factors on parenting.
Results
Examined individually, coldness was consistently associated with risk for a broad range of adult psychopathology. Averaged odds of psychiatric disorders associated with parenting were increased between 26 and 36 %. When the three parenting dimensions were examined together, coldness remained significant for major depression, phobia, and generalized anxiety disorder. Controlling for other disorders, the associations between the parenting dimensions and psychopathology were non-specific. Twin fitting model demonstrated that modest heritability accounted for parenting, whereas most variance resulted from the non-shared environment.
Conclusions
Based on our current and prior findings, there is broad similarity in the impact of parenting on adult psychopathology between men and women.
doi:10.1007/s00127-013-0656-4
PMCID: PMC3661760  PMID: 23344783
Parenting; Mental disorders; Population-based; Twins
12.  Structure of Genetic and Environmental Risk Factors for Symptoms of DSM-IV Borderline Personality Disorder 
JAMA psychiatry  2013;70(11):1206-1214.
IMPORTANCE
Previous studies have indicated that the psychopathological dimensions of borderline personality disorder (BPD) are influenced by a unitary liability factor. However, to our knowledge, the underlying etiological nature of the individual criteria for BPD as defined by the DSM-IV has not been explored.
OBJECTIVE
To determine the structure of genetic and environmental risk factors for the symptoms of BPD.
DESIGN, SETTING, AND PARTICIPANTS
Multivariate twin study with BPD criteria assessed by personal interview within a general community setting. Participants included 2794 young adults from the Norwegian Institute of Public Health Twin Panel.
MAIN OUTCOMES AND MEASURES
The 9 criteria for BPD assessed by the Structured Interview for DSM-IV Personality.
RESULTS
A common pathway model dominated by 1 highly heritable (55%) general BPD factor that strongly influenced all 9 BPD criteria (standardized path coefficients, 0.53–0.79) fit the data best. The model also included 2 additional common liability factors, mainly influencing criteria reflecting the affective and interpersonal dimensions. Both of these were mostly influenced by environmental liability factors (heritability, 29.3% and 2.2%). With 1 exception (criterion 2, unstable and intense relationships), the specific criteria were strongly influenced by environmental factors. Five of the 9 criterion-specific genetic effects were either 0 or negligible.
CONCLUSIONS AND RELEVANCE
These results indicate that most of the genetic effects on the individual BPD criteria derive from 1 highly heritable general BPD factor, whereas the environmental influences were mostly criterion specific.
doi:10.1001/jamapsychiatry.2013.1944
PMCID: PMC3927987  PMID: 24048243
13.  Childhood Trauma and Personality Disorder Criterion Counts: A Co-twin Control Analysis 
Journal of abnormal psychology  2013;122(4):1070-1076.
Correlational studies consistently report relationships between childhood trauma (CT) and most personality disorder (PD) criteria and diagnoses. However, it is not clear whether CT is directly related to PDs or whether common familial factors (i.e., shared environment and/or genetic factors) better account for that relationship. The current study used a co-twin control design to examine support for a direct effect of CT on PD criterion counts. Participants were from the Norwegian Twin Registry (N = 2,780), including a subset (n = 898) of twin pairs (449 pairs, 45% monozygotic [MZ]) discordant for CT meeting DSM–IV Posttraumatic Stress Disorder Criterion A. All participants completed the Norwegian version of the Structured Interview for DSM–IV Personality. Significant associations between CT and all PD criterion counts were detected in the general sample; however, the magnitude of observed effects was small, with CT accounting for no more than approximately 1% of variance in PD criterion counts. A significant, yet modest, interactive effect was detected for sex and CT on Schizoid and Schizotypal PD criterion counts, with CT being related to these disorders among women but not men. After common familial factors were accounted for in the discordant twin sample, CT was significantly related to Borderline and Antisocial PD criterion counts, but no other disorders; however, the magnitude of observed effects was quite modest (r2 = .006 for both outcomes), indicating that the small effect observed in the full sample is likely better accounted for by common genetic and/or environmental factors. CT does not appear to be a key factor in PD etiology.
doi:10.1037/a0034238
PMCID: PMC3992260  PMID: 24364608
trauma; personality disorders; co-twin control analysis; stress; twin study
14.  Immigrant enclaves and risk of diabetes: a prospective study 
BMC Public Health  2014;14(1):1093.
Background
The diversity of the Swedish population has increased substantially over the past three decades. The aim of this study was to assess whether living in an ethnic enclave is associated with risk of diabetes mellitus (DM) among first and second-generation immigrants and native Swedes.
Methods
Cumulative incidence of DM in three urban municipalities was assessed from 2006–2010 by linking records from the national census, multi-generational family register, and prescription drug register. Immigrant enclaves were identified using Moran’s Index. Multi-level logistic regression was used to assess the relationship between enclave residence and risk of DM for three groups: Iraqi immigrants, non-Iraqi immigrants, and native Swedes (N = 887,603).
Results
The cumulative incidence of DM was greater in Iraqi enclaves compared to other neighborhoods (4.7% vs. 2.3%). Among Iraqi immigrants, enclave residence was not associated with odds of DM (Odds ratio (OR): 1.03, 95% Confidence Interval (CI): 0.86 – 1.24). Among other immigrants, enclave residence was not associated with DM after accounting for neighborhood deprivation. Among native Swedes, enclave residence was associated with elevated risk of DM even after accounting for neighborhood deprivation and individual-level characteristics (OR: 1.23, 95% CI: 1.11 – 1.36).
Conclusions
Residential ethnic composition is associated with DM but this relationship differs across ethnic group. Enclave residence is not associated with increased odds of DM for immigrants, regardless of their nation of origin, but it is associated with increased likelihood of DM for native Swedes.
doi:10.1186/1471-2458-14-1093
PMCID: PMC4221671  PMID: 25335856
15.  Psychiatric resilience: longitudinal twin study 
Objective
There is great variability in response to stressful life events (SLEs), with some individuals demonstrating substantial psychiatric symptoms while others remain largely asymptomatic. The source of this variability is poorly understood. The present study aimed to examine the genetic and environmental underpinning of resilience, defined as the difference between the twins’ total score on a broad measure of internalizing symptoms and their predicted score based on their cumulative exposure to SLEs.
Method
SLE exposure and internalizing symptoms were assessed at two time points in 7,500 adult twins. Using the residual between actual and predicted internalizing symptom total score, twin modeling was conducted for each wave separately, as well as longitudinally. Quantitative and qualitative sex effects were also tested.
Results
Resilience was found to have a mild to moderate genetic heritability at each individual wave (~31%). Additionally, qualitative sex effects were found. Incorporating error of measurement into the model increased the estimated heritability for the latent construct of resilience (~50%). Unconfounded by measurement error and occasion specific effects, environmental influences contributed roughly equally to determining the individual level of resilience.
Conclusions
Genetic factors influence the level of psychiatric resilience, and are largely stable over time. The genes that impact on resilience are not entirely the same in males and females, although the degree of heritability is equal across the sexes. Environmental influences can also have an enduring effect on resilience. The present findings of the genetic and environmental influences on adaptation to SLEs clarify the sources of individual variation to environmental stressors.
doi:10.1192/bjp.bp.113.130906
PMCID: PMC4180845  PMID: 24723629
16.  Smoking and Major Depressive Disorder in Chinese Women 
PLoS ONE  2014;9(9):e106287.
Objective
To investigate the risk factors that contribute to smoking in female patients with major depressive disorder (MDD) and the clinical features in depressed smokers.
Methods
We examined the smoking status and clinical features in 6120 Han Chinese women with MDD (DSM-IV) between 30 and 60 years of age across China. Logistic regression was used to determine the association between clinical features of MDD and smoking status and between risk factors for MDD and smoking status.
Results
Among the recurrent MDD patients there were 216(3.6%) current smokers, 117 (2.0%) former smokers and 333(5.6%) lifetime smokers. Lifetime smokers had a slightly more severe illness, characterized by more episodes, longer duration, more comorbid illness (panic and phobias), with more DSM-IV A criteria and reported more symptoms of fatigue and suicidal ideation or attempts than never smokers. Some known risk factors for MDD were also differentially represented among smokers compared to non-smokers. Smokers reported more stressful life events, were more likely to report childhood sexual abuse, had higher levels of neuroticism and an increased rate of familial MDD. Only neuroticism was significantly related to nicotine dependence.
Conclusions
Although depressed women smokers experience more severe illness, smoking rates remain low in MDD patients. Family history of MDD and environmental factors contribute to lifetime smoking in Chinese women, consistent with the hypothesis that the association of smoking and depression may be caused by common underlying factors.
doi:10.1371/journal.pone.0106287
PMCID: PMC4152240  PMID: 25180682
17.  Depression, neighborhood deprivation and risk of type 2 diabetes 
Health & place  2013;23:63-69.
Neighborhood characteristics have been associated with both depression and diabetes, but to date little attention has been paid to whether the association between depression and diabetes varies across different types of neighborhoods. This prospective study examined the relationship between depression, neighborhood deprivation, and risk of type 2 diabetes among 336,340 adults from a national-representative sample of primary care centers in Sweden (2001–2007). Multi-level logistic regression models were used to assess associations between depression and risk of type 2 diabetes across affluent and deprived neighborhoods. After accounting for demographic, individual-level socioeconomic, and health characteristics, depression was significantly associated with risk of diabetes (odds ratio (OR): 1.10, 95% confidence interval (CI): 1.06–1.14), as was neighborhood deprivation (OR for high vs. low deprivation: 1.66, 95% CI: 1.22–1.34). The interaction term between depression and neighborhood deprivation was non-significant, indicating that the relationship between depression and diabetes risk is similar across levels of neighborhood socioeconomic deprivation.
doi:10.1016/j.healthplace.2013.05.004
PMCID: PMC3773725  PMID: 23771166
Depression; Type 2 diabetes mellitus; Residence characteristics; Multi-level analysis; Socioeconomic factors
18.  Adolescent Alcohol Use is Predicted by Childhood Temperament Factors Before Age 5, with Mediation Through Personality and Peers 
Alcoholism, clinical and experimental research  2013;37(12):10.1111/acer.12206.
Background:
Very few studies chart developmental pathways from early childhood to adolescent alcohol-related outcomes. We test whether measures of temperament collected from mothers at multiple assessments from 6 months through 5 years predict alcohol-related outcomes in mid-adolescence, the developmental pathways that mediate these effects, and whether there are gender differences in pathways of risk.
Methods:
Structural models were fit to longitudinal data from the Avon Longitudinal Study of Parents and Children, an epidemiological sample of pregnant women with delivery dates between April 1991 and December 1992, with children followed longitudinally. Temperamental characteristics were assessed at 6 time points from 6 to 69 months of age. Alcohol use and problems were assessed at age 15.5. Analyses here utilize data from 6,504 boys and 6,143 girls.
Results:
Childhood temperament prior to age 5 predicted adolescent alcohol use and problems at age 15.5 years, even after controlling for socio-demographic factors and parental alcohol problems. In both boys and girls, 2 largely uncorrelated and distinct temperament styles—children who were rated as having consistent emotional and conduct difficulties through age 5, and children who were rated as consistently sociable through age 5—both showed elevated rates of alcohol problems at age 15.5, but via different mediational pathways. In both genders, the association between emotional and conduct difficulties and alcohol problems was mediated through reduced conscientiousness and lower emotional stability. The association between sociability and alcohol problems was mediated through increased extraversion and sensation-seeking for both genders. Boys also showed mediation for sociability and alcohol outcomes through friendship characteristics, and girls through lower conscientiousness and reduced emotional stability.
Conclusions:
Our findings support multiple pathways to alcohol consumption and problems in adolescence. Some of these pathways are shared in boys and girls, while other risk factors are more salient in one gender or the other.
doi:10.1111/acer.12206
PMCID: PMC3823677  PMID: 23841856
ALSPAC; Temperament; Alcohol; Adolescence; Sex Differences
19.  The association between depressive symptoms from early to late adolescence and later use and harmful use of alcohol 
European Child & Adolescent Psychiatry  2014;23(12):1219-1230.
Depressive symptoms and alcohol misuse contribute substantially to the global health burden. These phenotypes often manifest, and frequently co-occur, during adolescence. However, few studies have examined whether both baseline levels of depressive symptoms and change in symptoms are associated with alcohol outcomes. In addition, inconsistent findings could be due to sex differences or the use of different alcohol outcomes. Using data from a prospective population-based cohort in the UK, we estimated trajectories of depressive symptoms from 12 years 10 months to 17 years 10 months, separately for male and female participants. We assessed whether baseline and change in depressive symptoms were associated with use and harmful use of alcohol at 18 years 8 months. Among females, increasing depressive symptoms were associated with increased alcohol use; whilst for males, there was little evidence of this. When examining harmful levels of alcohol use, baseline levels of depressive symptoms in males were weakly related to later harmful alcohol use but this association was attenuated substantially through adjustment for confounders. In contrast, both baseline symptoms and increase in symptoms were associated with later harmful alcohol use in females and these associations were not diminished by confounder adjustment. Elevated depressive symptoms during adolescence are positively associated with increases in both use and harmful use of alcohol at 18 years 8 months. These findings differ between the sexes. Further research is needed to examine the mechanisms underlying the link between depressive symptoms and harmful alcohol use to identify potentially modifiable factors for intervention.
Electronic supplementary material
The online version of this article (doi:10.1007/s00787-014-0600-5) contains supplementary material, which is available to authorized users.
doi:10.1007/s00787-014-0600-5
PMCID: PMC4246124  PMID: 25130265
ALSPAC; Adolescence; Depressive symptoms; Alcohol; Longitudinal
20.  Conduct problem trajectories and alcohol use and misuse in mid to late adolescence 
Drug and alcohol dependence  2013;133(1):100-107.
Background
We consider the strength of the relationship between types of conduct problems in early life and pattern of alcohol use during adolescence.
Methods
Children from the Avon Longitudinal Study of Parents and Children, a UK birth-cohort, had their level of conduct problems assessed repeatedly from 4 to 13 years using the maternal report Strengths and Difficulties Questionnaire. Developmental trajectories derived from these data were subsequently related to (i) patterns of alcohol use from 13 to 15 years, and (ii) hazardous alcohol used at age 16.
Results
Boys with ‘Adolescent Onset’ or ‘Early Onset Persistent’ conduct problems were much more likely to be high frequency drinkers between 13 and 15 years (OR 5.00 95% CI = [2.4, 10.6] and 3.9 95% CI = [2.1, 7.3] respectively) compared with those with Low or ‘Childhood Limited’ conduct. Adolescent Onset/Early Onset Persistent girls also had greater odds of this high-alcohol frequency drinking pattern (2.67 [1.4, 5.0] and 2.14 [1.2, 4.0] respectively). Associations were more moderate for risk of hazardous alcohol use at age 16. Compared to 32% among those with low conduct problems, over 40% of young people classified as showing Adolescent Onset/Early Onset Persistent conduct problems were drinking hazardously (OR 1.52 [1.09, 2.11] and 1.63 [1.22, 2.18] respectively).
Conclusions
Whilst persistent conduct problems greatly increase the risk of adolescent alcohol problems, the majority of adolescents reporting hazardous use at age 16 lack such a history. It is important, therefore, to undertake alcohol prevention among all young people as a priority, as well as target people with manifest conduct problems.
doi:10.1016/j.drugalcdep.2013.05.025
PMCID: PMC3786043  PMID: 23787037
ALSPAC; Conduct problems; Alcohol use; Adolescence; Trajectory
21.  Genetic and Environmental Contributions to Long-Term Sick Leave and Disability Pension: A Population-Based Study of Young Adult Norwegian Twins 
Although exclusion from the workforce due to long-term sick leave (LTSL) and disability pension (DP) is a major problem in many Western countries, the etiology of LTSL and DP is not well understood. These phenomena have a strong association as most patients receiving DP have first been on LTSL. However, only a few of those on LTSL end up with DP. The present study aimed to investigate the common and specific genetic and environmental risk factors for LTSL and DP. The present study utilizes a population-based sample of 7,710 young adult twins from the Norwegian Institute of Public Health Twin Panel, which has been linked to the Historical-Event Database (FD-Trygd; 1998–2008). Univariate and bivariate twin models were fitted to determine to what degree genetic and environmental factors contribute to variation in LTSL and DP. The estimated heritabilities of LTSL and DP were 0.49 and 0.66, respectively. There was no evidence for shared environmental or sex-specific factors. The phenotypic-, genetic-, and non-familial environmental correlations between the variables were 0.86, 0.82, and 0.94, respectively. Our results indicate that familial transmission of LTSL and DP is due to genetic and not environmental factors. The risk factors contributing to LTSL and DP were mainly shared, suggesting that what increases risk for LTSL also increases risk for DP. However, a non-negligible part of the genetic variance was not shared between the variables, which may contribute to explaining why some progress from LTSL to DP, whereas others return to work.
doi:10.1017/thg.2013.36
PMCID: PMC3800163  PMID: 23743022
long-term sick leave; disability pension; twin studies
22.  Two non-synonymous markers in PTPN21, identified by genome-wide association study data-mining and replication, are associated with schizophrenia 
Schizophrenia research  2011;131(0):43-51.
We conducted data-mining analyses of genome wide association (GWA) studies of the CATIE and MGS-GAIN datasets, and found 13 markers in the two physically linked genes, PTPN21 and EML5, showing nominally significant association with schizophrenia. Linkage disequilibrium (LD) analysis indicated that all 7 markers from PTPN21 shared high LD (r2>0.8), including rs2274736 and rs2401751, the two non-synonymous markers with the most significant association signals (rs2401751, P=1.10×10−3 and rs2274736, P=1.21×10−3). In a meta-analysis of all 13 replication datasets with a total of 13,940 subjects, we found that the two non-synonymous markers are significantly associated with schizophrenia (rs2274736, OR=0.92, 95% CI: 0.86–0.97, P=5.45×10−3 and rs2401751, OR = 0.92, 95% CI: 0.86–0.97, P=5.29×10−3). One SNP (rs7147796) in EML5 is also significantly associated with the disease (OR = 1.08, 95% CI: 1.02-1.14, P=6.43×10−3). These 3 markers remain significant after Bonferroni correction. Furthermore, haplotype conditioned analyses indicated that the association signals observed between rs2274736/rs2401751 and rs7147796 are statistically independent. Given the results that 2 non-synonymous markers in PTPN21 are associated with schizophrenia, further investigation of this locus is warranted.
doi:10.1016/j.schres.2011.06.023
PMCID: PMC4117700  PMID: 21752600
Data-mining; Informatic prioritization; Genetic association study; PTPN21; Non-synonymous SNP
23.  EVIDENCE FOR DISTINCT GENETIC EFFECTS ASSOCIATED WITH RESPONSE TO 35% CO2 
Depression and anxiety  2013;30(3):259-266.
Background
Carbon dioxide (CO2) hypersensitivity represents an individual difference response to breathing CO2 enriched air. People with a history of panic attacks or panic disorder are particularly prone to anxious response, suggesting that CO2 hypersensitivity is a robust risk marker of panic spectrum vulnerability.
Methods
Twin pairs (n = 346) from the general population-based Norwegian NIPH Mental Health Study completed a measure of anxiety before and after vital capacity inhalation of 35% CO2 air and before and after inhalation of regular air. Three hypotheses regarding genetic factors for CO2 hypersensitivity were examined: (1) a single set of genetic risk factors impacts anxiety before exposure to CO2 and these same genes constitute the only genetic influences on anxiety in response to CO2, (2) the genetic effects on pre-CO2 anxiety are entirely different from the genetic effects on anxiety in response to exposure to CO2 (i.e., new genetic effects), and (3) pre-CO2 anxiety influences anxiety in response to CO2 as well as unique genetic factors that become activated by respiratory stimulation.
Results
Our results support the latter hypothesis for response to 35% CO2, with additive genetic and unique environmental factors best fitting the data. Evidence of new genetic effects was observed, accounting for 20% unique variance in post 35% CO2 anxiety response. New genetic effects were not observed for anxiety ratings made post regular air where only preregular air anxiety ratings explained significant variance in this outcome.
Conclusions
These data suggest that there are distinct genetic factors associated with responsivity to respiratory stimulation via 35% CO2.
doi:10.1002/da.22038
PMCID: PMC4096694  PMID: 23349098
panic; carbon dioxide sensitivity; twins; genetic; panic disorder; anxiety
24.  The AVPR1A Gene and Substance Use Disorders: Association, Replication, and Functional Evidence 
Biological psychiatry  2011;70(6):519-527.
Background
The liability to addiction has been shown to be highly genetically correlated across drug classes, suggesting nondrug-specific mechanisms.
Methods
In 757 subjects, we performed association analysis between 1536 single nucleotide polymorphisms (SNPs) in 106 candidate genes and a drug use disorder diagnosis (DUD).
Results
Associations (p ≤ .0008) were detected with three SNPs in the arginine vasopressin 1A receptor gene, AVPR1A, with a gene-wise p value of 3 × 10−5. Bioinformatic evidence points to a role for rs11174811 (microRNA binding site disruption) in AVPR1A function. Based on literature implicating AVPR1A in social bonding, we tested spousal satisfaction as a mediator of the association of rs11174811 with the DUD. Spousal satisfaction was significantly associated with DUD in males (p <.0001). The functional AVPR1A SNP, rs11174811, was associated with spousal satisfaction in males (p = .007). Spousal satisfaction was a significant mediator of the relationship between rs11174811 and DUD. We also present replication of the association in males between rs11174811 and substance use in one clinically ascertained (n = 1399) and one epidemiologic sample (n = 2231). The direction of the association is consistent across the clinically-ascertained samples but reversed in the epidemiologic sample. Lastly, we found a significant impact of rs11174811 genotype on AVPR1A expression in a postmortem brain sample.
Conclusions
The findings of this study call for expansion of research into the role of the arginine vasopressin and other neuropeptide system variation in DUD liability.
doi:10.1016/j.biopsych.2011.02.023
PMCID: PMC4083653  PMID: 21514569
Addiction; alcoholism; gene systems; genetic association; social relationships; vasopressin
25.  Integrating Social Science and Behavioral Genetics: Testing the Origin of Socioeconomic Disparities in Depression Using a Genetically Informed Design 
American journal of public health  2013;103(0 1):S145-S151.
Objectives
We tested 3 hypotheses – social causation, social drift, and common cause – regarding the origin of socioeconomic disparities in major depression and determined whether the relationship between socioeconomic status (SES) and major depression varied by genetic liability for major depression.
Methods
Data were from a sample of female twins in the baseline Virginia Adult Twin Study of Psychiatric and Substance Use Disorders interviewed between 1987 and 1989 (n = 2153). We used logistic regression and structural equation twin models to evaluate these 3 hypotheses.
Results
Consistent with the social causation hypothesis, education (odds ratio [OR] = 0.78; 95% confidence interval [CI] = 0.66, 0.93; P < .01) and income (OR = 0.93; 95% CI = 0.89, 0.98; P < .01) were significantly related to past-year major depression. Upward social mobility was associated with lower risk of depression. There was no evidence that childhood SES was related to development of major depression (OR = 0.98; 95% CI =0.89, 1.09; P > .1). Consistent with a common genetic cause, there was a negative correlation between the genetic components of major depression and education (r2 = −0.22). Co-twin control analyses indicated a protective effect of education and income on major depression even after accounting for genetic liability.
Conclusions
This study utilized a genetically informed design to address how social position relates to major depression. Results generally supported the social causation model.
doi:10.2105/AJPH.2013.301247
PMCID: PMC3786755  PMID: 23927513

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