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STUDY QUESTION Which genetic factors regulate female propensity for giving birth to spontaneous dizygotic (DZ) twins? SUMMARY ANSWER We identified four new loci, GNRH1 , FSHR , ZFPM1 , and IPO8 , in addition to previously identified loci, FSHB and SMAD3. WHAT IS KNOWN ALREADY The propensity to give birth to DZ twins runs in families. Earlier, we reported that FSHB and SMAD3 as associated with DZ twinning and female fertility measures. STUDY DESIGN, SIZE, DURATION We conducted a genome-wide association meta-analysis (GWAMA) of mothers of spontaneous dizygotic (DZ) twins (8265 cases, 264 567 controls) and of independent DZ twin offspring (26 252 cases, 417 433 controls). PARTICIPANTS/MATERIALS, SETTING, METHODS Over 700 000 mothers of DZ twins, twin individuals and singletons from large cohorts in Australia/New Zealand, Europe, and the USA were carefully screened to exclude twins born after use of ARTs. Genetic association analyses by cohort were followed by meta-analysis, phenome wide association studies (PheWAS), in silico and in vivo annotations, and Zebrafish functional validation. MAIN RESULTS AND THE ROLE OF CHANCE This study enlarges the sample size considerably from previous efforts, finding four genome-wide significant loci, including two novel signals and a further two novel genes that are implicated by gene level enrichment analyses. The novel loci, GNRH1 and FSHR , have well-established roles in female reproduction whereas ZFPM1 and IPO8 have not previously been implicated in female fertility. We found significant genetic correlations with multiple aspects of female reproduction and body size as well as evidence for significant selection against DZ twinning during human evolution. The 26 top single nucleotide polymorphisms (SNPs) from our GWAMA in European-origin participants weakly predicted the crude twinning rates in 47 non-European populations (r  = 0.23 between risk score and population prevalence, s.e. 0.11, 1-tail P = 0.058) indicating that genome-wide association studies (GWAS) are needed in African and Asian populations to explore the causes of their respectively high and low DZ twinning rates. In vivo functional tests in zebrafish for IPO8 validated its essential role in female, but not male, fertility. In most regions, risk SNPs linked to known expression quantitative trait loci (eQTLs). Top SNPs were associated with in vivo reproductive hormone levels with the top pathways including hormone ligand binding receptors and the ovulation cycle. LARGE SCALE DATA The full DZT GWAS summary statistics will made available after publication through the GWAS catalog (https://www.ebi.ac.uk/gwas/). LIMITATIONS, REASONS FOR CAUTION Our study only included European ancestry cohorts. Inclusion of data from Africa (with the highest twining rate) and Asia (with the lowest rate) would illuminate further the biology of twinning and female fertility. WIDER IMPLICATIONS OF THE FINDINGS About one in 40 babies born in the world is a twin and there is much speculation on why twinning runs in families. We hope our results will inform investigations of ovarian response in new and existing ARTs and the causes of female infertility. STUDY FUNDING/COMPETING INTEREST(S) Support for the Netherlands Twin Register came from the Netherlands Organization for Scientific Research (NWO) and The Netherlands Organization for Health Research and Development (ZonMW) grants, 904-61-193, 480-04-004, 400-05-717, Addiction-31160008, 911-09-032, Biobanking and Biomolecular Resources Research Infrastructure (BBMRI.NL, 184.021.007), Royal Netherlands Academy of Science Professor Award (PAH/6635) to DIB, European Research Council (ERC-230374), Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06), the Avera Institute, Sioux Falls, South Dakota (USA) and the National Institutes of Health (NIH R01 HD042157-01A1) and the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health and Grand Opportunity grants 1RC2 MH089951. The QIMR Berghofer Medical Research Institute (QIMR) study was supported by grants from the National Health and Medical Research Council (NHMRC) of Australia (241944, 339462, 389927, 389875, 389891, 389892, 389938, 443036, 442915, 442981, 496610, 496739, 552485, 552498, 1050208, 1075175). L.Y. is funded by Australian Research Council (Grant number DE200100425). The Minnesota Center for Twin and Family Research (MCTFR) was supported in part by USPHS Grants from the National Institute on Alcohol Abuse and Alcoholism (AA09367 and AA11886) and the National Institute on Drug Abuse (DA05147, DA13240, and DA024417). The Women's Genome Health Study (WGHS) was funded by the National Heart, Lung, and Blood Institute (HL043851 and HL080467) and the National Cancer Institute (CA047988 and UM1CA182913), with support for genotyping provided by Amgen. Data collection in the Finnish Twin Registry has been supported by the Wellcome Trust Sanger Institute, the Broad Institute, ENGAGE—European Network for Genetic and Genomic Epidemiology, FP7-HEALTH-F4-2007, grant agreement number 201413, National Institute of Alcohol Abuse and Alcoholism (grants AA-12502, AA-00145, AA-09203, AA15416, and K02AA018755) and the Academy of Finland (grants 100499, 205585, 118555, 141054, 264146, 308248, 312073 and 336823 to J. Kaprio). TwinsUK is funded by the Wellcome Trust, Medical Research Council, Versus Arthritis, European Union Horizon 2020, Chronic Disease Research Foundation (CDRF), Zoe Ltd and the National Institute for Health Research (NIHR) Clinical Research Network (CRN) and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. For NESDA, funding was obtained from the Netherlands Organization for Scientific Research (Geestkracht program grant 10000-1002), the Center for Medical Systems Biology (CSMB, NVVO Genomics), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL), VU University's Institutes for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam, University Medical Center Groningen, Leiden University Medical Center, National Institutes of Health (NIH, ROI D0042157-01A, MH081802, Grand Opportunity grants 1 RC2 Ml-1089951 and IRC2 MH089995). Part of the genotyping and analyses were funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health. Computing was supported by BiG Grid, the Dutch e-Science Grid, which is financially supported by NWO. Work in the Del Bene lab was supported by the Programme Investissements d'Avenir IHU FOReSIGHT (ANR-18-IAHU-01). C.R. was supported by an EU Horizon 2020 Marie Skłodowska-Curie Action fellowship (H2020-MSCA-IF-2014 #661527). H.S. and K.S. are employees of deCODE Genetics/Amgen. The other authors declare no competing financial interests. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

Adolescence and early adulthood is a time when peer groups become increasingly influential in the lives of young people. Youths exposed to deviant peers risk susceptibility to externalizing behaviors and related psychopathology. In addition to environmental correlates of deviant peer affiliation, a growing body of evidence has suggested that affiliation with deviant peers is heritable. This study examined the magnitude of genetic and environmental influences on affiliation with deviant peers, changes in the relative importance of these factors, and which of these factors contribute to the stability of affiliation across this critical developmental period using a longitudinal twin study design that assessed same-sex twins (485 monozygotic pairs, 271 dizygotic pairs) at 3 discrete ages: 15, 18, and 21 years of age. Biometric models revealed that genetic influences increased with age. New genetic influences appeared during late adolescence, and no new genetic influences emerged by age 21. Environmental influences shared by sibling pairs decreased with age, while the proportion of nonshared environmental effects unique to each individual remained relatively stable over the course of development. Shared environmental influences were largely age-overlapping, whereas nonshared environmental influences were largely age-specific. In summary, this study found variance in affiliation with deviant peers is explained by shared and nonshared environment effects as well as by genetic influences (46% by age 21), supporting the role of genetically influenced selection factors. The shared environment was almost exclusively responsible for the stability in late adolescence, while genetic influences were primarily responsible for stability in early adulthood.

Background: As more states pass recreational cannabis legalization (RCL), we must understand how RCL affects substance use. Objectives: The current study aims to examine the effect of RCL on lifetime and past-year use of cannabis, alcohol, tobacco, and other drugs, frequency of cannabis, alcohol, and tobacco use, couse of cannabis with alcohol and tobacco, and consequences from cannabis and alcohol use. Methods: We used a unique, co-twin control design of twin pairs who were discordant for living in a state with RCL between 2018 and 2021. The sample consisted of 3,830 adult twins (41% male), including 232 twin pairs discordant for RCL. Problems from alcohol and cannabis use were assessed via the Brief Marijuana Consequences Questionnaire and the Brief Young Adult Alcohol Consequences Questionnaire. Results: Results indicated that the twin living in an RCL state was more likely to endorse past-year cannabis use (OR = 1.56, p = .009), greater number of cannabis use days in the past 6 months (ß = 0.47, p = .019), but not more negative consequences from cannabis use (ß = 0.21, p = .456) compared to their co-twin in a non-RCL state. There were no differences within-twin pairs in frequency of alcohol use (ß=-0.05, p = .601), but the RCL twin reported fewer negative consequences from alcohol use (ß=-0.29, p = .016) compared to their co-twin in a non-RCL state. We did not observe any other differences within-twin pairs on other outcomes. Conclusion: These results suggest that living in an RCL state is associated with greater cannabis frequency but not more negative consequences from cannabis use than living in a non-RCL state. [ABSTRACT FROM AUTHOR]

Existing behavior-genetic research implicates substantial influence of heredity and modest influence of shared environment on reading achievement and reading disability. Applying DeFries-Fulker analysis to a combined sample of twins and adoptees (N = 4886, including 266 reading-disabled probands), the present study replicates prior findings of considerable heritability for both reading achievement and reading disability. A simple biometric model adequately described parent and offspring data (combined N = 9430 parents and offspring) across differing types of families present in the sample Analyses yielded a high heritability estimate (around 0.70) and a negligible shared-environmentality estimate for both reading achievement and reading disability. No evidence of gene x environment interaction was found for parental reading ability and parental educational attainment, the two moderators analyzed. (Contains 4 tables and 1 figure.)

There are two common approaches to sub-typing the well-documented heterogeneity within antisocial behavior: age-of-onset (i.e., childhood-onset versus adolescence-onset; see "Moffitt" 1993) and behavioral (i.e., physical aggression versus non-aggressive rule-breaking). These approaches appear to be associated, such that aggression is more characteristic of childhood-onset antisocial behavior whereas rule-breaking is linked to both child- and adolescence-onset antisocial behavior. However, it remains unclear which approach, if either, better explains the heterogeneity within antisocial behavior. We examined this question in a prospective sample of male twins, assessed at the ages of 11, 14, 17, and 24 years. Although the age-of-onset subtypes predicted adult antisocial behavior in the expected direction when analyzed alone, this association dissipated once we controlled for aggression and rule-breaking. Such findings suggest that the behavioral sub-types of antisocial behavior may be a stronger predictor of later antisocial outcomes than is its age-of-onset.

Although large epidemiological data sets can inform research on the etiology and development of borderline personality disorder (BPD), they rarely include BPD measures. In some cases, however, proxy measures can be constructed using instruments already in these data sets. In this study, the authors developed and validated a self-report measure of BPD from the Multidimensional Personality Questionnaire (MPQ). Items for the new instrument--the Minnesota BPD scale (MBPD)--were identified and refined using three large samples: undergraduates, community adolescent twins, and urban substance users. The authors determined the construct validity of the MBPD scale by examining its association with (a) diagnosed BPD, (b) questionnaire-reported BPD symptoms, and (c) clinical variables associated with BPD: suicidality, trauma, disinhibition, internalizing distress, and substance use. The authors also tested the MBPD scale in two prison inmate samples. Across samples, the MBPD scores correlated with BPD indices and external criteria and showed incremental validity above measures of negative affect, thus supporting its construct validity as a measure of BPD. (Contains 1 figure and 4 tables.)

Whether gender differences exist in the impairment associated with attention-deficit/hyperactivity disorder (ADHD) is still largely unknown, because most samples have few affected girls or include only one sex. The current study evaluated whether ADHD affects adjustment differently for girls than boys in a population-based cohort of 11-year-olds (520 girls, 478 boys). Those with a "DSM-IV" diagnosis of ADHD (predominantly inattentive, hyperactive-impulsive, or combined) were compared to those without ADHD on teacher, parent, and child reports of academics, peer relationships, self-concept, clinical symptoms, and treatment. Although boys and girls with ADHD experienced difficulties in all areas, girls with ADHD, especially the inattentive subtype, were more negatively affected in academics and peer relationships. Inattentive girls were less popular and more likely to be bullied than girls without ADHD, whereas inattentive boys were not. The social isolation experienced by many girls with ADHD deserves greater attention. (Contains 2 figures and 3 tables.)

Background: The maximum number of alcoholic drinks consumed in a single 24-hr period is an alcoholism-related phenotype with both face and empirical validity. It has been associated with severity of withdrawal symptoms and sensitivity to alcohol, genes implicated in alcohol metabolism, and amplitude of a measure of brain activity associated with externalizing disorders in general. In a previous study we found that the maximum number of drinks fathers had ever consumed in 24 hrs was associated with externalizing behaviors and disorders in preadolescent and adolescent children. The purpose of the present study was to determine whether maternal maximum consumption has similar correlates. Method: We examined associations between maternal maximum consumption and alcohol dependence, respectively, and disruptive disorders and substance-related problems in two large independent population-based cohorts of 17-year-old adolescents. Results: Maximum consumption was associated with conduct disorder, disruptive disorders in general, early substance use and misuse, and substance disorders in adolescent children regardless of sex. Associations were consistent across cohorts, providing internal replication. They also paralleled our previous findings regarding paternal status. They could not be explained by maternal alcohol dependence, effects of drinking during pregnancy, or paternal maximum consumption. They were not simple artifacts of the fact that maximum consumption is a continuous measure while alcohol dependence is dichotomous. Conclusions: Despite deriving from a single question about "lifetime behavior," parental maximum consumption appears to reflect vulnerability for mental health problems, especially substance-related ones, more directly than a diagnosis of alcohol dependence.

It has recently been argued that shared environmental influences are moderate, identifiable, and persistent sources of individual differences in most forms of child and adolescent psychopathology, including antisocial behavior. Unfortunately, prior studies examining the stability of shared environmental influences over time were limited by possible passive gene-environment correlations, shared informants effects, and/or common experiences of trauma. The current study sought to address each of these limitations. We examined adolescent self-reported antisocial behavior in a 3.5 year longitudinal sample of 610 biological and adoptive sibling pairs from the Sibling Interaction and Behavior Study (SIBS). Results revealed that 74-81% of shared environmental influences present at time 1 were also present at time 2, whereas most non-shared environmental influences (88-89%) were specific to a particular assessment period. Such results provide an important constructive replication of prior research, strongly suggesting that shared environmental contributions to antisocial behavior are systematic in nature.

The Dyadic Adjustment Scale (DAS; G. B. Spanier, 1976) is the most widely used inventory of relationship satisfaction in the social sciences, yet the question of whether it is measuring the same concept in men and women has never been addressed. In the current study, the authors examined the factor structure of the DAS in a sample of 900 currently married couples who participated in the Minnesota Twin Family Study. Confirmatory factor analysis was applied to a second-order factor solution with Spanier's four factors (Dyadic Consensus, Dyadic Satisfaction, Dyadic Cohesion, Affectional Expression) loading on one higher order factor (Relationship Adjustment), to test for measurement invariance across gender. The second-order solution was relatively invariant across gender, even when taking into account the nonindependent nature of the data. This suggests that the best conceptualization of the DAS is one of a gender-invariant measure of marital adjustment with four distinct subfactors and that differences between men and women on any of these constructs can be interpreted by both clinicians and researchers as true mean differences rather than measurement bias. (Contains 2 footnotes, 2 tables, and 1 figure.)

It has been argued that peers are the most important agent of adolescent socialization and, more specifically, that this socialization process occurs at the child-specific (or nonshared environmental) level (J. R. Harris, 1998; R. Plomin & Asbury, 2005). The authors sought to empirically evaluate this nonshared environmental peer influence hypothesis by examining the association between externalizing behaviors and deviant peer affiliation in a sample of 454 pairs of monozygotic (genetically identical) twins, assessed at ages 14 and 17, within a cross-lagged twin differences design. Results argued against a causal nonshared environmental influence of peer affiliation on the development of externalizing behaviors and in favor of nonshared environmental "selection." In particular, the twin with more externalizing behaviors at age 14 reported increased deviant peer affiliation relative to his or her co-twin 3 years later, regardless of his or her genetic predispositions toward externalizing behavior. Such findings suggest that adolescents with higher levels of externalizing behaviors select or shape (either intentionally or inadvertently) subsequent environmental experiences to involve increased affiliation with deviant peers. Implications are discussed. (Contains 3 tables and 1 figure.)

Background: Behavior genetic methods can help to elucidate gene-environment (G-E) interplay in the development of internalizing (INT) disorders (i.e., major depression and anxiety disorders). To date, however, no study has conducted a comprehensive analysis examining multiple environmental risk factors with the purpose of delineating general mechanisms of G-E influence in the development of INT disorders. Methods: The sample consisted of 1315 male and female twin pairs participating in the age 17 assessment of the Minnesota Twin Family Study. Quantitative G-E interplay models were used to examine how genetic and environmental risk for INT disorders changes as a function of environmental context. Multiple measures and informants were employed to construct composite measures of INT disorders and six environmental risk factors including: stressful life events, mother-child and father-child relationship problems, antisocial and prosocial peer affiliation, and academic achievement and engagement. Results: Significant moderation effects were detected between each environmental risk factor and INT such that in the context of greater environmental adversity, nonshared environmental factors became more important in the etiology of INT symptoms. Conclusion: Our results are consistent with the interpretation that environmental stressors have a causative effect on the emergence of INT disorders. The consistency of our results suggests a general mechanism of environmental influence on INT disorders regardless of the specific form of environmental risk.

This report used a population-representative longitudinal twin study with two birth cohorts to explore the association between intelligence and education by understanding how genetic and environmental influences on intelligence moderate genetic and environmental influences on school grades and educational attainment. Nonshared environmental influences on grades were strong when IQ was low, but decreased across the range of IQ. Shared environmental influences common to age 24 educational attainment and age 17 IQ were strong when IQ was low, but genetic influences common to IQ and education were strong when IQ was high. These results suggest that the causal mechanisms linking educational variables with intelligence differ for people with different levels of intelligence. (Contains 4 tables and 4 figures.)

Antisocial behavior increases in adolescence, particularly among those who perform poorly in school. As adolescents move into adulthood, both educational attainment and the extent to which antisocial behavior continues have implications for adolescents' abilities to take on constructive social roles. The authors used a population-representative longitudinal twin study to explore how links among genetic and environmental influences at ages 17 and 24 may be implicated in the developmental processes involved. At age 17, expression of both genetic and nonshared environmental vulnerabilities unique to antisocial behavior was greater among those with low GPA than among those with higher GPA. This suggested that maintenance of high GPA buffered the impact of both genetic and environmental influences encouraging antisocial behavior. When GPA was high, both genetic and environmental influences involved in both traits encouraged good school performance and restrained antisocial behavior. At age 24, however, correlated family environmental influences drove the association between educational attainment and antisocial behavior. Antisocial characteristics involving school performance and educational attainment that transcend generations may slot individuals into social categories that restrict opportunities and reinforce antisocial characteristics. (Contains 3 footnotes, 5 tables, and 4 figures.)

Several forms of eye movement dysfunction (EMD) are regarded as promising candidate endophenotypes of schizophrenia. Discrepancies in individual study results have led to inconsistent conclusions regarding particular aspects of EMD in relatives of schizophrenia patients. To quantitatively evaluate and compare the candidacy of smooth pursuit, saccade and fixation deficits in first-degree biological relatives, we conducted a set of meta-analytic investigations. Among 18 measures of EMD, memory-guided saccade accuracy and error rate, global smooth pursuit dysfunction, intrusive saccades during fixation, antisaccade error rate and smooth pursuit closed-loop gain emerged as best differentiating relatives from controls (standardized mean differences ranged from 0.46 to 0.66), with no significant differences among these measures. Anticipatory saccades, but no other smooth pursuit component measures were also increased in relatives. Visually-guided reflexive saccades were largely normal. Moderator analyses examining design characteristics revealed few variables affecting the magnitude of the meta-analytically observed effects. Moderate effect sizes of relatives v. controls in selective aspects of EMD supports their endophenotype potential. Future work should focus on facilitating endophenotype utility through attention to heterogeneity of EMD performance, relationships among forms of EMD, and application in molecular genetics studies. (Contains 2 tables and 6 figures.)