[Show abstract][Hide abstract] ABSTRACT: 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.
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).
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.
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.
[Show abstract][Hide abstract] ABSTRACT: 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?
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.
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.
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.
Preview · Article · Jan 2016 · International Journal of Epidemiology
[Show abstract][Hide abstract] ABSTRACT: Importance
Suicide attempts are common in individuals with eating disorders. More precise understanding of the mechanisms underlying their concomitant occurrence is needed.Objective
To examine the association between eating disorders and suicide attempts and whether familial risk factors contribute to the association.Design, Setting, and Participants
A Swedish birth cohort including individuals born in Sweden between January 1, 1979, and December 31, 2001, was followed up from age 6 years to December 31, 2009 (N = 2 268 786). Information was acquired from Swedish national registers. All individuals were linked to their biological full siblings, maternal half siblings, paternal half siblings, full cousins, and half cousins. Data analysis was conducted from October 5, 2014, to April 28, 2015.Main Outcomes and Measures
Eating disorders were captured by 3 variables (any eating disorder, anorexia nervosa, and bulimia nervosa) identified by any lifetime diagnoses recorded in the registers. Suicide attempts were defined as any suicide attempts, including death by suicide, recorded in the registers. We examined the association between eating disorders and death by suicide separately, but the study was underpowered to explore familial liability for this association.Results
Of 2 268 786 individuals, 15 457 females (1.40% of all females) and 991 males (0.09% of all males) had any eating disorder, 7680 females (0.70%) and 453 males (0.04%) had anorexia nervosa, and 3349 females (0.30%), and 61 males (0.01%) had bulimia nervosa. Individuals with any eating disorder had an increased risk (reported as odds ratio [95% CI]) of suicide attempts (5.28 [5.04-5.54]) and death by suicide (5.39 [4.00-7.25]). The risks were attenuated but remained significant after adjusting for comorbid major depressive disorder, anxiety disorder, and substance use disorder (suicide attempts: 1.82 [1.72-1.93]; death by suicide: 2.04 [1.49-2.80]). Similar results were found for anorexia nervosa (suicide attempts: crude, 4.42 [4.12-4.74] vs adjusted, 1.70 [1.56-1.85]; death by suicide: crude, 6.46 [4.38-9.54] vs adjusted, 2.67 [1.78-4.01]) and bulimia nervosa (suicide attempts: crude, 6.26 [5.73-6.85] vs adjusted, 1.88 [1.68-2.10]; death by suicide: crude, 4.45 [2.44-8.11] vs adjusted, 1.48 [0.81-2.72]). Individuals (index) who had a full sibling with any eating disorder had an increased risk of suicide attempts (1.41 [1.29-1.53]). The risk was attenuated for any eating disorder in more-distant relatives (maternal half siblings, 1.10 [0.90-1.34]; paternal half siblings, 1.21 [0.98-1.49]; full cousins, 1.11 [1.06-1.18]; half cousins, 0.90 [0.78-1.03]). This familial pattern remained stable after adjusting for the index individuals’ eating disorders. Similar patterns were found for anorexia nervosa and bulimia nervosa.Conclusions and Relevance
These results suggest an increased risk of suicide attempts in individuals with lifetime eating disorders and their relatives. The pattern of familial coaggregation suggests familial liability for the association between eating disorders and suicide. Psychiatric comorbidities partially explain this association, suggesting particularly high-risk presentations.
[Show abstract][Hide abstract] ABSTRACT: Background:
Depression around the time of pregnancy affects at least 1 in 8 women and treatment with selective serotonin re-uptake inhibitors (SSRIs) in pregnant women has been increasing, but research on adverse effects on the fetus have so far commonly used designs unable to account for confounding. We aimed to examine the effects of prenatal SSRI exposure on offspring size outcomes and gestational age, and disentangle whether associations observed were due to the medication or other factors.
We used a Swedish population-based cohort of 392 029 children and national registers to estimate the associations between prenatal exposure to SSRIs and depression on the outcomes birthweight, birth length, birth head circumference, gestational age at birth and preterm birth. A sub-sample of 1007 children was analysed in a within-family design that accounts for unmeasured parental genetic and environmental confounders.
Crude analyses revealed associations between prenatal SSRI exposure, and offspring birth size and gestational age. However, in the within-family analyses, only the association between SSRI exposure and reduced gestational age (-2.3 days; 95% confidence interval -3.8 to -0.8) was observed.
This study indicates that prenatal SSRI exposure may not be causally related to offspring birth size. Rather, our analyses suggest that the association could be caused by other underlying differences instead of the medication per se. A small reduction of gestational age was associated with SSRI exposure in the within-family analysis and could be due to either the exposure, or other factors changing between pregnancies.
No preview · Article · Jan 2016 · International Journal of Epidemiology
[Show abstract][Hide abstract] ABSTRACT: Intellectual disability (ID) occurs in almost 3% of newborns. Despite
substantial research, a fundamental question about its origin and
links to intelligence (IQ) still remains. ID has been shown to be
inherited and has been accepted as the extreme low of the normal IQ
distribution. However, ID displays a complex pattern of inheritance.
Previously, noninherited rare mutations were shown to contribute to
severe ID risk in individual families, but in the majority of cases
causes remain unknown. Common variants associated with ID risk in
the population have not been systematically established. Here we
evaluate the hypothesis, originally proposed almost 1 century ago,
that most ID is caused by the same genetic and environmental
influences responsible for the normal distribution of IQ, but that
severe ID is not. We studied more than 1,000,000 sibling pairs and
9,000 twin pairs assessed for IQ and for the presence of ID. We
evaluated whether genetic and environmental influences at the
extremes of the distribution are different from those operating in
the normal range. Here we show that factors influencing mild ID
(lowest 3% of IQ distribution) were similar to those influencing IQ in
the normal range. In contrast, the factors influencing severe ID
(lowest 0.5% of IQ distribution) differ from those influencing mild ID
or IQ scores in the normal range. Taken together, our results suggest
that most severe ID is a distinct condition, qualitatively different
from the preponderance of ID, which, in turn, represents the low
extreme of the normal distribution of intelligence.
Full-text · Article · Dec 2015 · Proceedings of the National Academy of Sciences
[Show abstract][Hide abstract] ABSTRACT: Elevated cerebrospinal fluid (CSF) levels of the glia-derived N-methyl-D-aspartic acid receptor antagonist kynurenic acid (KYNA) have consistently been implicated in schizophrenia and bipolar disorder. Here, we conducted a genome-wide association study based on CSF KYNA in bipolar disorder and found support for an association with a common variant within 1p21.3. After replication in an independent cohort, we linked this genetic variant-associated with reduced SNX7 expression-to positive psychotic symptoms and executive function deficits in bipolar disorder. A series of post-mortem brain tissue and in vitro experiments suggested SNX7 downregulation to result in a caspase-8-driven activation of interleukin-1β and a subsequent induction of the brain kynurenine pathway. The current study demonstrates the potential of using biomarkers in genetic studies of psychiatric disorders, and may help to identify novel drug targets in bipolar disorder.Molecular Psychiatry advance online publication, 15 December 2015; doi:10.1038/mp.2015.186.
Full-text · Article · Dec 2015 · Molecular Psychiatry
[Show abstract][Hide abstract] ABSTRACT: Children with attention-deficit/hyperactivity disorder (ADHD) are at increased risk of problematic alcohol and other substance use in adolescence. This study used data from an ongoing, prospective, population-based twin study of Swedish children and adolescents to evaluate the extent to which the association between ADHD symptoms and alcohol problems reflects a unique source of genetic or environmental risk related to ADHD versus a broader predisposition to youth externalizing behavior. We used all available data from same-sex monozygotic (MZ) and dizygotic (DZ) twins on ADHD symptoms in childhood (age 9/12; N = 15,549) and alcohol problems in late adolescence (age 18; N = 2,564). Consistent with prior longitudinal studies, the phenotypic association between hyperactive/impulsive ADHD symptoms and alcohol problems was small in magnitude, whereas the association for inattentive symptoms was even weaker. Additive genetic influences explained 99.8% of the association between hyperactive/impulsive symptoms and alcohol problems. Furthermore, we found that the genetic risk specifically associated with hyperactive/impulsive symptoms was attenuated when estimated in the context of externalizing behavior liability during childhood, of which ADHD symptoms were specific expressions. In sensitivity analyses exploring hyperactivity in mid-adolescence, we found a similar pattern of genetic associations. These results are consistent with previous findings of genetically driven overlap in the etiology of ADHD and problematic alcohol use. At least some of this co-occurrence may result from a general predisposition to externalizing behaviors in youth.
No preview · Article · Dec 2015 · American Journal of Medical Genetics Part B Neuropsychiatric Genetics
[Show abstract][Hide abstract] ABSTRACT: Background Given the frequency with which families change residences, the effects of childhood relocations have gained increasing research attention. Many researchers have demonstrated that childhood relocations are associated with a variety of adverse outcomes. However, drawing strong causal claims remains problematic due to uncontrolled confounding factors.
Method We utilized longitudinal, population-based Swedish registers to generate a nationally representative sample of offspring born 1983–1997 (n = 1 510 463). Using Cox regression and logistic regression, we examined the risk for numerous adverse outcomes after childhood relocation while controlling for measured covariates. To account for unmeasured genetic and environmental confounds, we also compared differentially exposed cousins and siblings.
Results In the cohort baseline model, each annual relocation was associated with risk for the adverse outcomes, including suicide attempt [hazard ratio (HR) 1.19, 95% confidence interval (CI) 1.19–1.20]. However, when accounting for offspring and parental covariates (HR 1.08, 95% CI 1.07–1.09), as well as genetic and environmental confounds shared by cousins (HR 1.07, 95% CI 1.05–1.09) and siblings (HR 1.00, 95% CI 0.97–1.04), the risk for suicide attempt attenuated. We found a commensurate pattern of results for severe mental illness, substance abuse, criminal convictions, and low academic achievement.
Conclusions Previous research may have overemphasized the independent association between relocations and later adverse outcomes. The results suggest that the association between childhood relocations and suicide attempt, psychiatric problems, and low academic achievement is partially explained by genetic and environmental confounds correlated with relocations. This study demonstrates the importance of using family-based, quasi-experimental designs to test plausible alternate hypotheses when examining causality.
No preview · Article · Dec 2015 · Psychological Medicine
[Show abstract][Hide abstract] ABSTRACT: Several twin studies have investigated the overlap between attention deficit hyperactivity disorder (ADHD) and externalizing problems; however, limited information is known regarding the genetic and environmental contribution to the overlap between ADHD and internalizing problems. This study examined the genetic and environmental influences on the variation in and covariation between ADHD symptoms and internalizing problems by using the Child Behavior Checklist (CBCL). We investigated 1,316 child and adolescent twins, including 780 monozygotic twins and 536 dizygotic twins, aged 6 years to 18 years from the Chinese Child and Adolescent Twin Registry. ADHD symptoms and internalizing problems were quantified through parent rating by using the Attention Problems Scale and other three scales, which include Anxious/Depressed, Withdrawn, and Somatic Complaints of CBCL. Genetic and environmental susceptibilities common to ADHD symptoms and internalizing problems were examined through bivariate twin modeling. Results showed that genetic factors substantially influenced the ADHD symptoms with a heritability of 72%. Modest genetic influences and substantial shared environmental influences (20–77%) were observed in the three internalizing problem scales. Common genetic and shared environmental influences were essential for the overlap between ADHD and the three internalizing problems respectively. Approximately one-fifth of the genetic variance of ADHD symptoms was shared with anxiety/depression. In conclusion, substantial genetic and shared environmental influences on ADHD symptoms and internalizing problems were observed in Chinese children and adolescents. Our finding supports a common etiology between ADHD and internalizing problems. This finding can also help explain the co-existence of these behavior problems.
No preview · Article · Dec 2015 · American Journal of Medical Genetics Part B Neuropsychiatric Genetics
[Show abstract][Hide abstract] ABSTRACT: Prominent developmental theories posit a causal link between early-life exposures and later functioning. Yet, observed associations with early exposures may not reflect causal effects because of genetic and environmental confounding. The current manuscript describes how a systematic series of epidemiologic analyses that combine several genetically-informative designs and statistical approaches can help distinguish between competing theories. In particular, the manuscript details how combining the use of measured covariates with sibling-comparisons, cousin-comparisons, and additional designs can help elucidate the sources of covariation between early-life exposures and later outcomes, including the roles of (a) factors that are not shared in families, including a potential causal effect of the exposure; (b) carryover effects from the exposure of one child to the next; and (c) familial confounding. We also describe key assumptions and how they can be critically evaluated. Furthermore, we outline how subsequent analyses, including effect decomposition with respect to measured, plausible mediators, and quantitative genetic models can help further specify the underlying processes that account for the associations between early-life exposures and offspring outcomes.
No preview · Article · Nov 2015 · Behavior Genetics
[Show abstract][Hide abstract] ABSTRACT: Couples are similar in their pair-bonding behavior, yet the reasons for this similarity are often unclear. A common explanation is phenotypic assortment, whereby individuals select partners with similar heritable characteristics. Alternatively, social homogamy, whereby individuals passively select partners with similar characteristic due to shared social backgrounds, is rarely considered. We examined whether phenotypic assortment and/or social homogamy can contribute to mate similarity using a twin-partner design. The sample came from the Twin and Offspring Study in Sweden, which included 876 male and female monozygotic and same-sex dizygotic twins plus their married or cohabitating partners. Results showed that variance in pair-bonding behavior was attributable to genetic and nonshared environmental factors. Furthermore, phenotypic assortment accounted for couple similarity in pair-bonding behavior. This suggests that individuals' genetically based characteristics are involved in their selection of mates with similar pair-bonding behavior.
No preview · Article · Nov 2015 · Behavior Genetics
[Show abstract][Hide abstract] ABSTRACT: Background
Mortality has been suggested to be increased in autism spectrum disorder (ASD).AimsTo examine both all-cause and cause-specific mortality in ASD, as well as investigate moderating role of gender and intellectual ability.Method
Odds ratios (ORs) were calculated for a population-based cohort of ASD probands (n = 27 122, diagnosed between 1987 and 2009) compared with gender-, age- and county of residence-matched controls (n = 2 672 185).ResultsDuring the observed period, 24 358 (0.91%) individuals in the general population died, whereas the corresponding figure for individuals with ASD was 706 (2.60%; OR = 2.56; 95% CI 2.38-2.76). Cause-specific analyses showed elevated mortality in ASD for almost all analysed diagnostic categories. Mortality and patterns for cause-specific mortality were partly moderated by gender and general intellectual ability.Conclusions
Premature mortality was markedly increased in ASD owing to a multitude of medical conditions.
Full-text · Article · Nov 2015 · The British Journal of Psychiatry
[Show abstract][Hide abstract] ABSTRACT: Lithium is the mainstay prophylactic treatment for bipolar disorder (BD), but treatment response varies considerably across individuals. Patients who respond well to lithium treatment might represent a relatively homogeneous subtype of this genetically and phenotypically diverse disorder. Here, we performed genome-wide association studies (GWAS) to identify (i) specific genetic variations influencing lithium response and (ii) genetic variants associated with risk for lithium-responsive BD. Patients with BD and controls were recruited from Sweden and the United Kingdom. GWAS were performed on 2698 patients with subjectively defined (self-reported) lithium response and 1176 patients with objectively defined (clinically documented) lithium response. We next conducted GWAS comparing lithium responders with healthy controls (1639 subjective responders and 8899 controls; 323 objective responders and 6684 controls). Meta-analyses of Swedish and UK results revealed no significant associations with lithium response within the bipolar subjects. However, when comparing lithium-responsive patients with controls, two imputed markers attained genome-wide significant associations, among which one was validated in confirmatory genotyping (rs116323614, P=2.74 × 10−8). It is an intronic single-nucleotide polymorphism (SNP) on chromosome 2q31.2 in the gene SEC14 and spectrin domains 1 (SESTD1), which encodes a protein involved in regulation of phospholipids. Phospholipids have been strongly implicated as lithium treatment targets. Furthermore, we estimated the proportion of variance for lithium-responsive BD explained by common variants (‘SNP heritability’) as 0.25 and 0.29 using two definitions of lithium response. Our results revealed a genetic variant in SESTD1 associated with risk for lithium-responsive BD, suggesting that the understanding of BD etiology could be furthered by focusing on this subtype of BD.
Full-text · Article · Oct 2015 · Molecular Psychiatry
[Show abstract][Hide abstract] ABSTRACT: Acute intermittent porphyria (AIP) has been associated with schizophrenia in some studies, but prior research is limited by the absence of comparison populations. Here, we linked Swedish registers to examine the risk of schizophrenia and bipolar disorder in 717 individuals diagnosed with AIP and their first-degree relatives, compared with matched individuals without AIP and their first-degree relatives. Individuals with AIP had a fourfold increased risk of schizophrenia or bipolar disorder. Similarly, relatives of individuals with AIP had double the risk of schizophrenia or bipolar disorder, suggesting that these associations may be as a result of common genetic influences.
No preview · Article · Oct 2015 · The British journal of psychiatry: the journal of mental science
[Show abstract][Hide abstract] ABSTRACT: In epidemiological and twin populations, prior interview studies have identified an externalizing spectrum of disorders. Could this be detected utilizing objective registry data? In 20,603 twin pairs from the Swedish Twin Registry, we obtained information from national medical, criminal and pharmacy records on drug abuse (DA), criminal behavior (CB) and alcohol use disorders (AUD). Multivariate twin modeling was performed with the OpenMx package. A common pathway model with quantitative but not qualitative sex effects fit best with twin resemblance for the latent liability to externalizing syndromes due to both genetic and shared environmental factors. Heritability of the liability was higher in females (76 vs. 62 %) while shared environmental influences were considerably stronger in males (23 vs. 3 %). In both sexes, this latent liability was most strongly indexed by DA and least by CB. All three syndromes had specific genetic influences (especially CB and AUD in males, and CB in females) and specific shared environmental effects (especially DA and CB in males, and AUD in females). For DA, CB and AUD in men, and DA and AUD in women, at least 75 % of the genetic risk arose through the common factor. The best fit model assumed that genetic and environmental influences on these externalizing syndromes in males and females were the same. We identified, in registry data, a highly heritable externalizing spectrum. DA, CB and AUD share substantial genetic and modest to moderate shared environmental influences. The nature of the externalizing spectrum differed meaningfully between the sexes.
No preview · Article · Oct 2015 · Behavior Genetics
[Show abstract][Hide abstract] ABSTRACT: Studies suggest associations between childhood autistic traits and adolescent psychotic experiences. However, recent research suggests that a general neuropsychiatric problems factor predicts adverse outcomes better than specific diagnostic entities. To examine if the alleged association between autistic traits and psychotic experiences could rather be explained by a general neuropsychiatric problems factor comprising symptoms of ADHD, tic disorder, developmental coordination disorder, and learning disorder, we conducted a prospective cohort study based on the Child and Adolescent Twin Study in Sweden. In addition, we examined the genetic and environmental influences on the associations. A total of 9,282 twins with data on childhood autistic traits and other neuropsychiatric problems, and follow-up data on psychotic experiences at ages 15 and/or 18 years were included. First, psychotic experiences were regressed on autistic traits and second, the general neuropsychiatric problems factor was added to the model. Auditory hallucinations were analyzed separately from the other psychotic experiences. Finally, twin analyses were employed to disentangle genetic from environmental influences in the observed associations. Replicating prior research, significant associations were found between autistic traits in childhood and auditory hallucinations at ages 15 and 18. However, after controlling for the general neuropsychiatric problems factor, the associations between autistic traits and auditory hallucinations disappeared, whereas the association between the general neuropsychiatric problems factor and auditory hallucinations persisted after controlling for autistic traits. Twin analyses revealed that the association between the general neuropsychiatric problems factor and auditory hallucinations was driven by shared genetic influences.
Full-text · Article · Oct 2015 · American Journal of Medical Genetics Part B Neuropsychiatric Genetics