Publications by authors named "Joanna Martin"

45 Publications

Sex differences in anxiety and depression in children with attention deficit hyperactivity disorder: Investigating genetic liability and comorbidity.

Am J Med Genet B Neuropsychiatr Genet 2021 May 3. Epub 2021 May 3.

MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.

It is unknown why attention deficit hyperactivity disorder (ADHD) is more common in males, whereas anxiety and depression show a female population excess. We tested the hypothesis that anxiety and depression risk alleles manifest as ADHD in males. We also tested whether anxiety and depression in children with ADHD show a different etiology to typical anxiety and depression and whether this differs by sex. The primary clinical ADHD sample consisted of 885 (14% female) children. Psychiatric symptoms were assessed using standardized interviews. Polygenic risk scores (PRS) were derived using large genetic studies. Replication samples included independent clinical ADHD samples (N = 3,794; 25.7% female) and broadly defined population ADHD samples (N = 995; 33.4% female). We did not identify sex differences in anxiety or depression PRS in children with ADHD. In the primary sample, anxiety PRS were associated with social and generalized anxiety in males, with evidence of a sex-by-PRS interaction for social anxiety. These results did not replicate in the broadly defined ADHD sample. Depression PRS were not associated with comorbid depression symptoms. The results suggest that anxiety and depression genetic risks are not more likely to lead to ADHD in males. Also, the evidence for shared etiology between anxiety symptoms in those with ADHD and typical anxiety was weak and needs replication.
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http://dx.doi.org/10.1002/ajmg.b.32842DOI Listing
May 2021

Examining the association between childhood autistic traits and adolescent hypomania: a longitudinal twin study.

Psychol Med 2021 Apr 8:1-10. Epub 2021 Apr 8.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Background: There is evidence that autism spectrum disorders (ASDs) co-occur with bipolar disorder (BD) relatively frequently. Individuals with BD often report symptoms of mania and hypomania during adolescence, prior to the age of onset for BD. It is unknown whether these symptoms are associated with ASDs. We examined whether diagnoses of ASDs and autistic traits were associated with hypomania in a large, population-based Swedish twin sample.

Methods: Parental structured interviews assessed autistic traits, and were used to assign screening diagnoses of ASDs, when twins were aged 9 or 12 (N = 13 533 pairs). Parents then completed questionnaires assessing hypomania when the twins were aged 15 and 18 (N = 3852 pairs at age 15, and 3013 pairs at age 18). After investigating the phenotypic associations between these measures, we used the classical twin design to test whether genetic and environmental influences on autistic traits influence variation in adolescent hypomania.

Results: Autistic traits and ASD diagnoses in childhood were associated with elevated scores on the measures of adolescent hypomania. Twin analyses indicated that 6-9% of the variance in hypomania was explained by genetic influences that were shared with autistic traits in childhood. When repeating these analyses for specific autistic trait domains, we found a stronger association between social interaction difficulties and hypomania than for other autistic trait domains.

Conclusions: These results indicate a genetic link between autistic traits and hypomania in adolescence. This adds to the growing evidence base of genetic factors associated with ASDs showing links with psychiatric outcomes across childhood and into adulthood.
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http://dx.doi.org/10.1017/S0033291721000374DOI Listing
April 2021

Insights into attention-deficit/hyperactivity disorder from recent genetic studies.

Psychol Med 2021 Apr 5:1-13. Epub 2021 Apr 5.

MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.

Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable neurodevelopmental disorder (NDD). In this narrative review, we summarize recent advances in quantitative and molecular genetic research from the past 5-10 years. Combined with large-scale international collaboration, these advances have resulted in fast-paced progress in understanding the etiology of ADHD and how genetic risk factors map on to clinical heterogeneity. Studies are converging on a number of key insights. First, ADHD is a highly polygenic NDD with a complex genetic architecture encompassing risk variants across the spectrum of allelic frequencies, which are implicated in neurobiological processes. Second, genetic studies strongly suggest that ADHD diagnosis shares a large proportion of genetic risks with continuously distributed traits of ADHD in the population, with shared genetic risks also seen across development and sex. Third, ADHD genetic risks are shared with those implicated in many other neurodevelopmental, psychiatric and somatic phenotypes. As sample sizes and the diversity of genetic studies continue to increase through international collaborative efforts, we anticipate further success with gene discovery, characterization of how the ADHD phenotype relates to other human traits and growing potential to use genomic risk factors for understanding clinical trajectories and for precision medicine approaches.
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http://dx.doi.org/10.1017/S0033291721000982DOI Listing
April 2021

Investigating regions of shared genetic variation in attention deficit/hyperactivity disorder and major depressive disorder: a GWAS meta-analysis.

Sci Rep 2021 Apr 1;11(1):7353. Epub 2021 Apr 1.

MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.

Attention deficit/hyperactivity disorder (ADHD) demonstrates a high level of comorbidity with major depressive disorder (MDD). One possible contributor to this is that the two disorders show high genetic correlation. However, the specific regions of the genome that may be responsible for this overlap are unclear. To identify variants associated with both ADHD and MDD, we performed a meta-analysis of GWAS of ADHD and MDD. All genome wide significant (p < 5 × 10) SNPs in the meta-analysis that were also strongly associated (p < 5 × 10) independently with each disorder were followed up. These putatively pleiotropic SNPs were tested for additional associations across a broad range of phenotypes. Fourteen linkage disequilibrium-independent SNPs were associated with each disorder separately (p < 5 × 10) and in the cross-disorder meta-analysis (p < 5 × 10). Nine of these SNPs had not been highlighted previously in either individual GWAS. Evidence supported nine of the fourteen SNPs acting as eQTL and two as brain eQTL. Index SNPs and their genomic regions demonstrated associations with other mental health phenotypes. Through conducting meta-analysis on ADHD and MDD only, our results build upon the previously observed genetic correlation between ADHD and MDD and reveal novel genomic regions that may be implicated in this overlap.
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http://dx.doi.org/10.1038/s41598-021-86802-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016853PMC
April 2021

Examining Sex-Differentiated Genetic Effects Across Neuropsychiatric and Behavioral Traits.

Biol Psychiatry 2021 Jan 9. Epub 2021 Jan 9.

Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Background: The origin of sex differences in prevalence and presentation of neuropsychiatric and behavioral traits is largely unknown. Given established genetic contributions and correlations, we tested for a sex-differentiated genetic architecture within and between traits.

Methods: Using European ancestry genome-wide association summary statistics for 20 neuropsychiatric and behavioral traits, we tested for sex differences in single nucleotide polymorphism (SNP)-based heritability and genetic correlation (r < 1). For each trait, we computed per-SNP z scores from sex-stratified regression coefficients and identified genes with sex-differentiated effects using a gene-based approach. We calculated correlation coefficients between z scores to test for shared sex-differentiated effects. Finally, we tested for sex differences in across-trait genetic correlations.

Results: We observed no consistent sex differences in SNP-based heritability. Between-sex, within-trait genetic correlations were high, although <1 for educational attainment and risk-taking behavior. We identified 4 genes with significant sex-differentiated effects across 3 traits. Several trait pairs shared sex-differentiated effects. The top genes with sex-differentiated effects were enriched for multiple gene sets, including neuron- and synapse-related sets. Most between-trait genetic correlation estimates were not significantly different between sexes, with exceptions (educational attainment and risk-taking behavior).

Conclusions: Sex differences in the common autosomal genetic architecture of neuropsychiatric and behavioral phenotypes are small and polygenic and unlikely to fully account for observed sex-differentiated attributes. Larger sample sizes are needed to identify sex-differentiated effects for most traits. For well-powered studies, we identified genes with sex-differentiated effects that were enriched for neuron-related and other biological functions. This work motivates further investigation of genetic and environmental influences on sex differences.
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http://dx.doi.org/10.1016/j.biopsych.2020.12.024DOI Listing
January 2021

Polygenic association between attention-deficit/hyperactivity disorder liability and cognitive impairments.

Psychol Med 2021 Feb 3:1-9. Epub 2021 Feb 3.

Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Background: A recent genome-wide association study (GWAS) identified 12 independent loci significantly associated with attention-deficit/hyperactivity disorder (ADHD). Polygenic risk scores (PRS), derived from the GWAS, can be used to assess genetic overlap between ADHD and other traits. Using ADHD samples from several international sites, we derived PRS for ADHD from the recent GWAS to test whether genetic variants that contribute to ADHD also influence two cognitive functions that show strong association with ADHD: attention regulation and response inhibition, captured by reaction time variability (RTV) and commission errors (CE).

Methods: The discovery GWAS included 19 099 ADHD cases and 34 194 control participants. The combined target sample included 845 people with ADHD (age: 8-40 years). RTV and CE were available from reaction time and response inhibition tasks. ADHD PRS were calculated from the GWAS using a leave-one-study-out approach. Regression analyses were run to investigate whether ADHD PRS were associated with CE and RTV. Results across sites were combined via random effect meta-analyses.

Results: When combining the studies in meta-analyses, results were significant for RTV (R2 = 0.011, β = 0.088, p = 0.02) but not for CE (R2 = 0.011, β = 0.013, p = 0.732). No significant association was found between ADHD PRS and RTV or CE in any sample individually (p > 0.10).

Conclusions: We detected a significant association between PRS for ADHD and RTV (but not CE) in individuals with ADHD, suggesting that common genetic risk variants for ADHD influence attention regulation.
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http://dx.doi.org/10.1017/S0033291720005218DOI Listing
February 2021

Meeting the guidelines: Implementing a distress screening intervention for veterans with cancer.

Psychooncology 2020 12 10;29(12):2067-2074. Epub 2020 Oct 10.

Section of Palliative Care, Department of Medicine, Jesse Brown VA Medical Center, Chicago, Illinois, USA.

Background: Guidelines recommend systematic evaluation of distress screening and referral for cancer patients. Implementation remains a notable gap for cancer centers serving disadvantaged communities. We present the implementation of a distress screening program within a Veterans Affairs hospital oncology clinic, serving a majority African American (AA) male population of low socioeconomic status (SES).

Methods: The Coleman Foundation funded this program supporting a palliative care physician and psychologist to implement screening in a phased approach as follows: (1) Organizing key stakeholders, (2) educating clinical staff, (3) delivering distress screening, (4) generating documentation, and (5) implementing clinical action and referral pathways. We utilized validated measures in the "Patient Screening Questions for Supportive Care" screening tool.

Results: This program was unsuccessful in screening all veterans with cancer; however, we were able to implement 3 years of longitudinal screening. In distress screens from the initial program period (n = 253), patients were primarily males (95.6%) of older age (m = 70, standard deviation = 9.45), AA (76.4%), with various cancers of advanced disease (69%). Males reported moderate psychosocial distress and elevated financial needs. For males with elevated psychosocial distress (n = 63, PHQ-4 ≥3), 36% were previously connected with psychosocial services. Following screening, engagement increased as the majority (77%) established psychosocial care.

Conclusions: This screening program had mixed success. Centralized program staff and available supportive care referrals were critical for program implementation. Screening may have increased engagement in social work/mental health services for males of low SES. Screening programs should be tailored to the needs of underserved communities with accessible housing/food subsidies.
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http://dx.doi.org/10.1002/pon.5565DOI Listing
December 2020

Antimicrobial stewardship in remote primary healthcare across northern Australia.

PeerJ 2020 22;8:e9409. Epub 2020 Jul 22.

The Peter Doherty Institute for Infection and Immunity, The Royal Melbourne Hospital and The University of Melbourne, Melbourne, Victoria, Australia.

Background: The high burden of infectious disease and associated antimicrobial use likely contribute to the emergence of antimicrobial resistance in remote Australian Aboriginal communities. We aimed to develop and apply context-specific tools to audit antimicrobial use in the remote primary healthcare setting.

Methods: We adapted the General Practice version of the National Antimicrobial Prescribing Survey (GP NAPS) tool to audit antimicrobial use over 2-3 weeks in 15 remote primary healthcare clinics across the Kimberley region of Western Australia (03/2018-06/2018), Top End of the Northern Territory (08/2017-09/2017) and far north Queensland (05/2018-06/2018). At each clinic we reviewed consecutive clinic presentations until 30 presentations where antimicrobials had been used were included in the audit. Data recorded included the antimicrobials used, indications and treating health professional. We assessed the appropriateness of antimicrobial use and functionality of the tool.

Results: We audited the use of 668 antimicrobials. Skin and soft tissue infections were the dominant treatment indications (WA: 35%; NT: 29%; QLD: 40%). Compared with other settings in Australia, narrow spectrum antimicrobials like benzathine benzylpenicillin were commonly given and the appropriateness of use was high (WA: 91%; NT: 82%; QLD: 65%). While the audit was informative, non-integration with practice software made the process manually intensive.

Conclusions: Patterns of antimicrobial use in remote primary care are different from other settings in Australia. The adapted GP NAPS tool functioned well in this pilot study and has the potential for integration into clinical care. Regular stewardship audits would be facilitated by improved data extraction systems.
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http://dx.doi.org/10.7717/peerj.9409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382366PMC
July 2020

Investigating gender-specific effects of familial risk for attention-deficit hyperactivity disorder and other neurodevelopmental disorders in the Swedish population.

BJPsych Open 2020 Jun 18;6(4):e65. Epub 2020 Jun 18.

Department of Medical Epidemiology & Biostatistics, Karolinska Institutet; and School of Medical Sciences, Örebro University, Sweden.

Background: Many psychiatric disorders show gender differences in prevalence. Recent studies suggest that female patients diagnosed with anxiety and depression carry more genetic risks related to attention-deficit hyperactivity disorder (ADHD) compared with affected males.

Aims: In this register-based study, we aimed to test whether female patients who received clinical diagnoses of anxiety, depressive, bipolar and eating disorders are at higher familial risk for ADHD and other neurodevelopmental disorders, compared with diagnosed male patients.

Method: We analysed data from a record-linkage of several Swedish national registers, including 151 025 sibling pairs from 103 941 unique index individuals diagnosed with anxiety, depressive, bipolar or eating disorders, as well as data from 646 948 cousin pairs. We compared the likelihood of having a relative diagnosed with ADHD/neurodevelopmental disorders in index males and females.

Results: Female patients with anxiety disorders were more likely than affected males to have a brother with ADHD (odd ratio (OR) = 1.13, 95% CI 1.05-1.22). Results for broader neurodevelopmental disorders were similar and were driven by ADHD diagnoses. Follow-up analyses revealed similar point estimates for several categories of anxiety disorders, with the strongest effect observed for agoraphobia (OR = 1.64, 95% CI 1.12-2.39). No significant associations were found in individuals with depressive, bipolar or eating disorders, or in cousins.

Conclusions: These results provide modest support for the possibility that familial/genetic risks for ADHD may show gender-specific phenotypic expression. Alternatively, there could be gender-specific biases in diagnoses of anxiety and ADHD. These factors could play a small role in the observed gender differences in prevalence of ADHD and anxiety.
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http://dx.doi.org/10.1192/bjo.2020.47DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7345736PMC
June 2020

A brief report: de novo copy number variants in children with attention deficit hyperactivity disorder.

Transl Psychiatry 2020 05 12;10(1):135. Epub 2020 May 12.

MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.

Recent case-control genetic studies of attention deficit hyperactivity disorder (ADHD) have implicated common and rare genetic risk alleles, highlighting the polygenic and complex aetiology of this neurodevelopmental disorder. Studies of other neurodevelopmental disorders, such as autism spectrum disorder (ASD), Tourette disorder, developmental delay/intellectual disability and schizophrenia indicate that identification of specific risk alleles and additional insights into disorder biology can be gained by studying non-inherited de novo variation. In this study, we aimed to identify large de novo copy number variants (CNVs) in children with ADHD. Children with a confirmed diagnosis of ADHD and their parents were genotyped and included in this sample. We used PennCNV to call large (>200 kb) CNVs and identified those calls that were present in the proband and absent in both biological parents. In 305 parent-offspring trios, we detected 14 de novo CNVs in 13 probands, giving a mutation rate of 4.6% and a per individual rate of 4.3%. This rate is higher than published reports in controls and similar to those observed for ASD, schizophrenia and Tourette disorder. We also identified de novo mutations at four genomic loci (15q13.1-13.2 duplication, 16p13.11 duplication, 16p12.2 deletion and 22q11.21 duplication) that have previously been implicated in other neurodevelopmental disorders, two of which (16p13.11 and 22q11.21) have also been implicated in case-control ADHD studies. Our study complements ADHD case-control genomic analyses and demonstrates the need for larger parent-offspring trio genetic studies to gain further insights into the complex aetiology of ADHD.
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http://dx.doi.org/10.1038/s41398-020-0821-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217839PMC
May 2020

What explains the link between childhood ADHD and adolescent depression? Investigating the role of peer relationships and academic attainment.

Eur Child Adolesc Psychiatry 2020 Nov 13;29(11):1581-1591. Epub 2020 Jan 13.

MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.

There is increasing evidence that childhood Attention-Deficit Hyperactivity Disorder (ADHD) elevates risk of later depression, but the mechanisms behind this association are unclear. We investigated the relationship between childhood ADHD symptoms and late-adolescent depressive symptoms in a population cohort, and examined whether academic attainment and peer problems mediated this association. ALSPAC (Avon Longitudinal Study of Parents and Children) is an ongoing prospective longitudinal population-based UK cohort that has collected data since September 1990. 2950 individuals with data on parent-reported ADHD symptoms in childhood (7.5 years) and self-reported depressive symptoms in late adolescence (17.5 years) were included in analyses. 2161 individuals with additional data at age 16 years on parent-reported peer problems as an indicator of peer relationships and formal examination results (General Certificate of Secondary Education; GCSE) as an indicator of academic attainment were included in mediation analyses. Childhood ADHD symptoms were associated with higher depressive symptoms (b = 0.49, SE = 0.11, p < 0.001) and an increased odds of clinically significant depressive symptoms in adolescence (OR = 1.27, 95% CI 1.15-1.41, p < 0.001). The association with depressive symptoms was mediated in part by peer problems and academic attainment which accounted for 14.68% and 20.13% of the total effect, respectively. Childhood ADHD is associated with increased risk of later depression. The relationship is mediated in part by peer relationships and academic attainment. This highlights peer relationships and academic attainment as potential targets of depression prevention and intervention in those with ADHD. Future research should investigate which aspects of peer relationships are important in conferring later risk for depression.
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http://dx.doi.org/10.1007/s00787-019-01463-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595988PMC
November 2020

Using Genetics to Examine a General Liability to Childhood Psychopathology.

Behav Genet 2020 07 11;50(4):213-220. Epub 2019 Dec 11.

Division of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Hadyn Ellis Building, Maindy Road, Cathays, Cardiff, CF24 4HQ, UK.

Psychiatric disorders show phenotypic as well as genetic overlaps. There are however also marked developmental changes throughout childhood. We investigated the extent to which, for a full range of early childhood psychopathology, a general "p" factor was explained by genetic liability, as indexed by multiple different psychiatric polygenic risk scores (PRS) and whether these relationships altered with age. The sample was a UK, prospective, population-based cohort with psychopathology data at age 7 (N = 8161) and age 13 (N = 7017). PRS were generated from large published genome-wide association studies. At both ages, we found evidence for a childhood "p" factor as well as for specific factors. Schizophrenia and attention-deficit/hyperactivity disorder (ADHD) PRS were associated with this general "p" factor at both ages but depression and autism spectrum disorder (ASD) PRS were not. We also found some evidence of associations between schizophrenia, ADHD and depression PRS with specific factors, but these were less robust and there was evidence for developmental changes.
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http://dx.doi.org/10.1007/s10519-019-09985-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355267PMC
July 2020

A Stepped-Wedge Randomized Controlled Trial: Effects of eHealth Interventions for Pain Control Among Adults With Cancer in Hospice.

J Pain Symptom Manage 2020 03 9;59(3):626-636. Epub 2019 Nov 9.

Department of Biopharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA; Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA; Jesse Brown VA Medical Center, Chicago, Illinois, USA.

Context: Unrelieved cancer pain at the end of life interferes with achieving patient-centered goals.

Objective: To compare effects of usual hospice care and PAINRelieveIt® on pain outcomes in patients and their lay caregivers.

Methods: In a five-step, stepped-wedge randomized, controlled study, 234 patients (49% male, 18% Hispanic, 51% racial minorities) and 231 lay caregivers (26% male, 20% Hispanic, 54% racial minorities) completed pre-pain/post-pain measures. They received usual hospice care with intervention components that included a summary of the patient's pain data, decision support for hospice nurses, and multimedia education tailored to the patient's and lay caregiver's misconceptions about pain.

Results: The intervention effect on analgesic adherence (primary outcome) was not significant. Post-test worst pain intensity was significantly higher for the experimental group, but the difference (0.70; CI = [0.12, 1.27]) was not clinically meaningful. There was nearly universal availability of prescriptions for strong opioids and adjuvant analgesics for neuropathic pain in both groups. Lay caregivers' pain misconceptions (0-5 scale) were significantly lower in the experimental group than the usual care group (mean difference controlling for baseline is 0.38; CI = [0.08, 0.67]; P = 0.01).

Conclusion: This randomized controlled trial was a negative trial for the primary study outcomes but positive for a secondary outcome. The trial is important for clearly demonstrating the feasibility of implementing the innovative set of interventions.
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http://dx.doi.org/10.1016/j.jpainsymman.2019.10.028DOI Listing
March 2020

Translating Discoveries in Attention-Deficit/Hyperactivity Disorder Genomics to an Outpatient Child and Adolescent Psychiatric Cohort.

J Am Acad Child Adolesc Psychiatry 2020 08 14;59(8):964-977. Epub 2019 Aug 14.

Center for Genomic Medicine, Massachusetts General Hospital, Boston; Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA; Massachusetts General Hospital and Harvard Medical School, Massachusetts General Hospital, Boston. Electronic address:

Objective: Genomic discoveries should be investigated in generalizable child psychiatric samples in order to justify and inform studies that will evaluate their use for specific clinical purposes. In youth consecutively referred for neuropsychiatric evaluation, we examined 1) the convergent and discriminant validity of attention-deficit/hyperactivity disorder (ADHD) polygenic risk scores (PRSs) in relation to DSM-based ADHD phenotypes; 2) the association of ADHD PRSs with phenotypes beyond ADHD that share its liability and have implications for outcome; and 3) the extent to which youth with high ADHD PRSs manifest a distinctive clinical profile.

Method: Participants were 433 youth, ages 7-18 years, from the Longitudinal Study of Genetic Influences on Cognition. We used logistic/linear regression and mixed effects models to examine associations with ADHD-related polygenic variation from the largest ADHD genome-wide association study to date. We replicated key findings in 5,140 adult patients from a local health system biobank.

Results: Among referred youth, ADHD PRSs were associated with ADHD diagnoses, cross-diagnostic ADHD symptoms and academic impairment (odds ratios ∼1.4; R values ∼2%-3%), as well as cross-diagnostic variation in aggression and working memory. In adults, ADHD PRSs were associated with ADHD and phenotypes beyond the condition that have public health implications. Finally, youth with a high ADHD polygenic burden showed a more severe clinical profile than youth with a low burden (β coefficients ∼.2).

Conclusion: Among child and adolescent outpatients, ADHD polygenic risk was associated with ADHD and related phenotypes as well as clinical severity. These results extend the scientific foundation for studies of ADHD polygenic risk in the clinical setting and highlight directions for further research.
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http://dx.doi.org/10.1016/j.jaac.2019.08.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408479PMC
August 2020

Associations Between Attention-Deficit/Hyperactivity Disorder and Various Eating Disorders: A Swedish Nationwide Population Study Using Multiple Genetically Informative Approaches.

Biol Psychiatry 2019 10 15;86(8):577-586. Epub 2019 May 15.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; School of Medical Sciences, Örebro University, Örebro, Sweden.

Background: Although attention-deficit/hyperactivity disorder (ADHD) and eating disorders (EDs) frequently co-occur, little is known about the shared etiology. In this study, we comprehensively investigated the genetic association between ADHD and various EDs, including anorexia nervosa (AN) and other EDs such as bulimia nervosa.

Methods: We applied different genetically informative designs to register-based information of a Swedish nationwide population (N = 3,550,118). We first examined the familial coaggregation of clinically diagnosed ADHD and EDs across multiple types of relatives. We then applied quantitative genetic modeling in full-sisters and maternal half-sisters to estimate the genetic correlations between ADHD and EDs. We further tested the associations between ADHD polygenic risk scores and ED symptoms, and between AN polygenic risk scores and ADHD symptoms, in a genotyped population-based sample (N = 13,472).

Results: Increased risk of all types of EDs was found in individuals with ADHD (any ED: odds ratio [OR] = 3.97, 95% confidence interval [CI] = 3.81, 4.14; AN: OR = 2.68, 95% CI = 2.15, 2.86; other EDs: OR = 4.66, 95% CI = 4.47, 4.87; bulimia nervosa: OR = 5.01, 95% CI = 4.63, 5.41) and their relatives compared with individuals without ADHD and their relatives. The magnitude of the associations decreased as the degree of relatedness decreased, suggesting shared familial liability between ADHD and EDs. Quantitative genetic models revealed stronger genetic correlation of ADHD with other EDs (.37, 95% CI = .31, .42) than with AN (.14, 95% CI = .05, .22). ADHD polygenic risk scores correlated positively with ED symptom measures overall and with the subscales Drive for Thinness and Body Dissatisfaction despite small effect sizes.

Conclusions: We observed stronger genetic association with ADHD for non-AN EDs than for AN, highlighting specific genetic correlation beyond a general genetic factor across psychiatric disorders.
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http://dx.doi.org/10.1016/j.biopsych.2019.04.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6776821PMC
October 2019

Identification of common genetic risk variants for autism spectrum disorder.

Nat Genet 2019 03 25;51(3):431-444. Epub 2019 Feb 25.

The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.
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http://dx.doi.org/10.1038/s41588-019-0344-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454898PMC
March 2019

Association of Genetic Risk Factors for Psychiatric Disorders and Traits of These Disorders in a Swedish Population Twin Sample.

JAMA Psychiatry 2019 03;76(3):280-289

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Importance: Psychiatric traits associated with categorically defined psychiatric disorders are heritable and present to varying degrees in the general population. It is commonly assumed that diagnoses represent the extreme end of continuously distributed traits in the population, but this assumption has yet to be robustly tested for many psychiatric phenotypes.

Objective: To assess whether genetic risk factors associated with psychiatric disorders are also associated with continuous variation in milder population traits.

Design, Setting, And Participants: This study combined a novel twin analytic approach with polygenic risk score (PRS) analyses in a large population-based twin sample. Phenotypic and genetic data were available from the Child and Adolescent Twin Study in Sweden. Inpatient data were available for January 1, 1987, to December 31, 2014, and outpatient data for January 1, 2001, to December 31, 2013. The last day of follow-up was December 31, 2014. Data analysis was performed from January 1, 2017, to September 30, 2017.

Main Outcomes And Measures: Questionnaires that assessed traits of autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), learning difficulties, tic disorders (TDs), obsessive-compulsive disorder (OCD), anxiety, major depressive disorder (MDD), mania, and psychotic experiences were administered to a large Swedish twin sample. Individuals with clinical psychiatric diagnoses were identified using the Swedish National Patient Register. Joint categorical/continuous twin modeling was used to estimate genetic correlations between psychiatric diagnoses and continuous traits. The PRSs for psychiatric disorders were calculated based on independent discovery genetic data. The association between PRSs for each disorder and associated continuous traits was tested.

Results: Phenotype data were available for 13 923 twin pairs (35.1% opposite sex and 31.7% same-sex females) at 9 years of age, 5165 pairs (36.9% opposite sex and 34.0% same-sex females) at 15 years of age, and 4273 pairs (36.5% opposite sex and 34.4% same-sex females) at 18 years of age. Genetic data were available for 13 412 individuals (50.2% females). Twin genetic correlations between numerous psychiatric diagnoses and corresponding traits ranged from 0.31 to 0.69. Disorder PRSs were associated with related population traits for ASD (β [SE] = 0.04 [0.01] at 9 years of age), ADHD (β [SE] = 0.27 [0.03] at 9 years of age), TDs (β [SE] = 0.02 [0.004] at 9 years of age), OCD (β [SE] = 0.13 [0.05] at 18 years of age), anxiety (β [SE] = 0.18 [0.08] at 9 years of age; β [SE] = 0.07 [0.02] at 15 years of age; and β [SE] = 0.40 [0.17] at 18 years of age), MDD (β [SE] = 0.10 [0.03] at 9 years of age; β [SE] = 0.11 [0.02] at 15 years of age; and β [SE] = 0.41 [0.10] at 18 years of age), and schizophrenia (β [SE] = 0.02 [0.01] at 18 years of age). Polygenic risk scores for depressive symptoms were associated with MDD diagnoses (odds ratio, 1.16; 95% CI, 1.02-1.32).

Conclusions And Relevance: These results suggest that genetic factors associated with psychiatric disorders are also associated with milder variation in characteristic traits throughout the general population for many psychiatric phenotypes. This study suggests that many psychiatric disorders are likely to be continuous phenotypes rather than the categorical entities currently defined in diagnostic manuals, which has strong implications for genetic research in particular.
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http://dx.doi.org/10.1001/jamapsychiatry.2018.3652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439816PMC
March 2019

Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder.

Nat Genet 2019 01 26;51(1):63-75. Epub 2018 Nov 26.

The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.
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http://dx.doi.org/10.1038/s41588-018-0269-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481311PMC
January 2019

Copy number variation and neuropsychiatric problems in females and males in the general population.

Am J Med Genet B Neuropsychiatr Genet 2019 09 11;180(6):341-350. Epub 2018 Oct 11.

Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Neurodevelopmental problems (NPs) are more common in males, whereas anxiety and depression are more common in females. Rare copy number variants (CNVs) have been implicated in neurodevelopmental disorders. The aim of this study was to characterize the relationship between rare CNVs with NPs, anxiety, and depression in a childhood population sample, as well as to examine sex-specific effects. We analyzed a sample of N = 12,982 children, of whom 5.3% had narrowly defined NPs (clinically diagnosed), 20.9% had broadly defined NPs (based on validated screening measures, but no diagnosis), and 3.0% had clinically diagnosed anxiety or depression. Rare (<1% frequency) CNVs were categorized by size (100-500 kb or > 500 kb), type, and putative relevance to NPs. We tested for association of CNV categories with outcomes and examined sex-specific effects. Medium deletions (OR[CI] = 1.18[1.05-1.33], p = .0053) and large duplications (OR[CI] = 1.45[1.19-1.75], p = .00017) were associated with broadly defined NPs. Large deletions (OR[CI] = 1.85[1.14-3.01], p = .013) were associated with narrowly defined NPs. There were no significant sex differences in CNV burden in individuals with NPs. Although CNVs were not associated with anxiety/depression in the whole sample, in individuals diagnosed with these disorders, females were more likely to have large CNVs (OR[CI] = 3.75[1.45-9.68], p = .0064). Rare CNVs are associated with both narrowly and broadly defined NPs in a general population sample of children. Our results also suggest that large, rare CNVs may show sex-specific phenotypic effects.
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http://dx.doi.org/10.1002/ajmg.b.32685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767107PMC
September 2019

Sex differences in predicting ADHD clinical diagnosis and pharmacological treatment.

Eur Child Adolesc Psychiatry 2019 Apr 10;28(4):481-489. Epub 2018 Aug 10.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

In youth, ADHD is more commonly diagnosed in males than females, but higher male-to-female ratios are found in clinical versus population-based samples, suggesting a sex bias in the process of receiving a clinical diagnosis of ADHD. This study investigated sex differences in the severity and presentation of ADHD symptoms, conduct problems, and learning problems in males and females with and without clinically diagnosed ADHD. We then investigated whether the predictive associations of these symptom domains on being diagnosed and treated for ADHD differed in males and females. Parents of 19,804 twins (50.64% male) from the Swedish population completed dimensional assessments of ADHD symptoms and co-occurring traits (conduct and learning problems) when children were aged 9 years. Children from this population sample were linked to Patient Register data on clinical ADHD diagnosis and medication prescriptions. At the population level, males had higher scores for all symptom domains (inattention, hyperactivity/impulsivity, conduct, and learning problems) compared to females, but similar severity was seen in clinically diagnosed males and females. Symptom severity for all domains increased the likelihood of receiving an ADHD diagnosis in both males and females. Prediction analyses revealed significant sex-by-symptom interactions on diagnostic and treatment status for hyperactivity/impulsivity and conduct problems. In females, these behaviours were stronger predictors of clinical diagnosis (hyperactivity/impulsivity: OR 1.08, 95% CI 1.01, 1.15; conduct: OR 1.43, 95% CI 1.09, 1.87), and prescription of pharmacological treatment (hyperactivity/impulsivity: OR 1.24, 95% CI 1.02, 1.50; conduct: OR 2.20, 95% CI 1.05, 4.63). Females with ADHD may be more easily missed in the ADHD diagnostic process and less likely to be prescribed medication unless they have prominent externalising problems.
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http://dx.doi.org/10.1007/s00787-018-1211-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445815PMC
April 2019

The contribution of common genetic risk variants for ADHD to a general factor of childhood psychopathology.

Mol Psychiatry 2020 08 22;25(8):1809-1821. Epub 2018 Jun 22.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Common genetic risk variants have been implicated in the etiology of clinical attention-deficit/hyperactivity disorder (ADHD) diagnoses and symptoms in the general population. However, given the extensive comorbidity across ADHD and other psychiatric conditions, the extent to which genetic variants associated with ADHD also influence broader psychopathology dimensions remains unclear. The aim of this study was to evaluate the associations between ADHD polygenic risk scores (PRS) and a broad range of childhood psychiatric symptoms, and to quantify the extent to which such associations can be attributed to a general factor of childhood psychopathology. We derived ADHD PRS for 13,457 children aged 9 or 12 from the Child and Adolescent Twin Study in Sweden, using results from an independent meta-analysis of genome-wide association studies of ADHD diagnosis and symptoms. We estimated associations between ADHD PRS, a general psychopathology factor, and several dimensions of neurodevelopmental, externalizing, and internalizing symptoms, using structural equation modeling. Higher ADHD PRS were statistically significantly associated with elevated neurodevelopmental, externalizing, and depressive symptoms (R = 0.26-1.69%), but not with anxiety. After accounting for a general psychopathology factor, on which all symptoms loaded positively (mean loading = 0.50, range = 0.09-0.91), an association with specific hyperactivity/impulsivity remained significant. ADHD PRS explained ~ 1% (p value < 0.0001) of the variance in the general psychopathology factor and ~ 0.50% (p value < 0.0001) in specific hyperactivity/impulsivity. Our results suggest that common genetic risk variants associated with ADHD, and captured by PRS, also influence a general genetic liability towards broad childhood psychopathology in the general population, in addition to a specific association with hyperactivity/impulsivity symptoms.
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http://dx.doi.org/10.1038/s41380-018-0109-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6169728PMC
August 2020

Association of copy number variation across the genome with neuropsychiatric traits in the general population.

Am J Med Genet B Neuropsychiatr Genet 2018 07 24;177(5):489-502. Epub 2018 Apr 24.

MRC Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, Bristol, United Kingdom.

Copy number variants (CNVs) are associated with psychiatric conditions in clinical populations. The relationship between rare CNV burden and neuropsychiatric traits in young, general populations is underexplored. A total of 6,807 children from the Avon Longitudinal Study of Parents and Children (ALSPAC) were studied. CNVs were inferred from single nucleotide polymorphism-array data using PennCNV. After excluding children with known candidate CNVs for schizophrenia (SCZ), rare (<1%) CNV burden (total number of genes affected by CNVs, total length of CNVs, and largest CNV carried) was analyzed in relation to: psychotic experiences (PEs) and anxiety/depression in adolescence; autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD), ASD and ADHD traits, and cognitive measures during childhood. Outcomes were also assessed in relation to known SCZ CNVs. The number of genes affected by rare CNVs was associated with a continuous measure of ASD: the standardized mean difference [SMD] per gene affected was increased by 0.018 [95%CI 0.011,0.025], p = 3e-07 for duplications and by 0.021 [95%CI 0.010, 0.032], p = 1e-04 for deletions. In line with our published results on educational attainment in ALSPAC, intelligence quotient (IQ) was associated with CNV burden: the SMD per gene affected was -0.017 [95%CI -0.025, -0.008] p = 1e-04 for duplications and -0.023 [95%CI -0.037, -0.009], p = .002 for deletions. Associations were also observed for measures of coherence, attention, memory, and social cognition. SCZ-associated deletions were associated with IQ (SMD: -0.617 [95%CI -0.936, -0.298], p = 2e-04), but not with PEs or other traits. We found that rare CNV burden and known SCZ candidate CNVs are associated with neuropsychiatric phenotypes in a nonclinically ascertained sample of young people.
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http://dx.doi.org/10.1002/ajmg.b.32637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099375PMC
July 2018

Sex-specific manifestation of genetic risk for attention deficit hyperactivity disorder in the general population.

J Child Psychol Psychiatry 2018 08 16;59(8):908-916. Epub 2018 Feb 16.

Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Background: Attention deficit hyperactivity disorder (ADHD) is more commonly diagnosed in males than in females. A growing body of research suggests that females with ADHD might be underdiagnosed or receive alternative diagnoses, such as anxiety or depression. Other lines of reasoning suggest that females might be protected from developing ADHD, requiring a higher burden of genetic risk to manifest the disorder.

Methods: We tested these two hypotheses, using common variant genetic data from two population-based cohorts. First, we tested whether females and males diagnosed with anxiety or depression differ in terms of their genetic risk for ADHD, assessed as polygenic risk scores (PRS). Second, we tested whether females and males with ADHD differed in ADHD genetic risk burden. We used three different diagnostic definitions: registry-based clinical diagnoses, screening-based research diagnoses and algorithm-based research diagnoses, to investigate possible referral biases.

Results: In individuals with a registry-based clinical diagnosis of anxiety or depression, females had higher ADHD PRS than males [OR(CI) = 1.39 (1.12-1.73)] but there was no sex difference for screening-based [OR(CI) = 1.15 (0.94-1.42)] or algorithm-based [OR(CI) = 1.04 (0.89-1.21)] diagnoses. There was also no sex difference in ADHD PRS in individuals with ADHD diagnoses that were registry-based [OR(CI) = 1.04 (0.84-1.30)], screening-based [OR(CI) = 0.96 (0.85-1.08)] or algorithm-based [OR(CI) = 1.15 (0.78-1.68)].

Conclusions: This study provides genetic evidence that ADHD risk may be more likely to manifest or be diagnosed as anxiety or depression in females than in males. Contrary to some earlier studies, the results do not support increased ADHD genetic risk in females with ADHD as compared to affected males.
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http://dx.doi.org/10.1111/jcpp.12874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6055636PMC
August 2018

A Genetic Investigation of Sex Bias in the Prevalence of Attention-Deficit/Hyperactivity Disorder.

Biol Psychiatry 2018 06 2;83(12):1044-1053. Epub 2017 Dec 2.

Stanley Center for Psychiatric Research, Broad Institute, Cambridge, Massachusetts; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts.

Background: Attention-deficit/hyperactivity disorder (ADHD) shows substantial heritability and is two to seven times more common in male individuals than in female individuals. We examined two putative genetic mechanisms underlying this sex bias: sex-specific heterogeneity and higher burden of risk in female cases.

Methods: We analyzed genome-wide autosomal common variants from the Psychiatric Genomics Consortium and iPSYCH Project (n = 20,183 cases, n = 35,191 controls) and Swedish population register data (n = 77,905 cases, n = 1,874,637 population controls).

Results: Genetic correlation analyses using two methods suggested near complete sharing of common variant effects across sexes, with r estimates close to 1. Analyses of population data, however, indicated that female individuals with ADHD may be at especially high risk for certain comorbid developmental conditions (i.e., autism spectrum disorder and congenital malformations), potentially indicating some clinical and etiological heterogeneity. Polygenic risk score analysis did not support a higher burden of ADHD common risk variants in female cases (odds ratio [confidence interval] = 1.02 [0.98-1.06], p = .28). In contrast, epidemiological sibling analyses revealed that the siblings of female individuals with ADHD are at higher familial risk for ADHD than the siblings of affected male individuals (odds ratio [confidence interval] = 1.14 [1.11-1.18], p = 1.5E-15).

Conclusions: Overall, this study supports a greater familial burden of risk in female individuals with ADHD and some clinical and etiological heterogeneity, based on epidemiological analyses. However, molecular genetic analyses suggest that autosomal common variants largely do not explain the sex bias in ADHD prevalence.
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http://dx.doi.org/10.1016/j.biopsych.2017.11.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992329PMC
June 2018

Assessing the evidence for shared genetic risks across psychiatric disorders and traits.

Psychol Med 2018 08 4;48(11):1759-1774. Epub 2017 Dec 4.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Genetic influences play a significant role in risk for psychiatric disorders, prompting numerous endeavors to further understand their underlying genetic architecture. In this paper, we summarize and review evidence from traditional twin studies and more recent genome-wide molecular genetic analyses regarding two important issues that have proven particularly informative for psychiatric genetic research. First, emerging results are beginning to suggest that genetic risk factors for some (but not all) clinically diagnosed psychiatric disorders or extreme manifestations of psychiatric traits in the population share genetic risks with quantitative variation in milder traits of the same disorder throughout the general population. Second, there is now evidence for substantial sharing of genetic risks across different psychiatric disorders. This extends to the level of characteristic traits throughout the population, with which some clinical disorders also share genetic risks. In this review, we summarize and evaluate the evidence for these two issues, for a range of psychiatric disorders. We then critically appraise putative interpretations regarding the potential meaning of genetic correlation across psychiatric phenotypes. We highlight several new methods and studies which are already using these insights into the genetic architecture of psychiatric disorders to gain additional understanding regarding the underlying biology of these disorders. We conclude by outlining opportunities for future research in this area.
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http://dx.doi.org/10.1017/S0033291717003440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6088770PMC
August 2018

Shared genetic influences between dimensional ASD and ADHD symptoms during child and adolescent development.

Mol Autism 2017 4;8:18. Epub 2017 Apr 4.

MRC Integrative Epidemiology Unit (MRC IEU), University of Bristol, Bristol, UK.

Background: Shared genetic influences between attention-deficit/hyperactivity disorder (ADHD) symptoms and autism spectrum disorder (ASD) symptoms have been reported. Cross-trait genetic relationships are, however, subject to dynamic changes during development. We investigated the continuity of genetic overlap between ASD and ADHD symptoms in a general population sample during childhood and adolescence. We also studied uni- and cross-dimensional trait-disorder links with respect to genetic ADHD and ASD risk.

Methods: Social-communication difficulties ( ≤ 5551, Social and Communication Disorders Checklist, SCDC) and combined hyperactive-impulsive/inattentive ADHD symptoms ( ≤ 5678, Strengths and Difficulties Questionnaire, SDQ-ADHD) were repeatedly measured in a UK birth cohort (ALSPAC, age 7 to 17 years). Genome-wide summary statistics on clinical ASD (5305 cases; 5305 pseudo-controls) and ADHD (4163 cases; 12,040 controls/pseudo-controls) were available from the Psychiatric Genomics Consortium. Genetic trait variances and genetic overlap between phenotypes were estimated using genome-wide data.

Results: In the general population, genetic influences for SCDC and SDQ-ADHD scores were shared throughout development. Genetic correlations across traits reached a similar strength and magnitude (cross-trait  ≤ 1,    3 × 10) as those between repeated measures of the same trait (within-trait  ≤ 0.94,    7 × 10). Shared genetic influences between traits, especially during later adolescence, may implicate variants in K-RAS signalling upregulated genes (-meta = 6.4 × 10). Uni-dimensionally, each population-based trait mapped to the expected behavioural continuum: risk-increasing alleles for clinical ADHD were persistently associated with SDQ-ADHD scores throughout development (marginal regression  = 0.084%). An age-specific genetic overlap between clinical ASD and social-communication difficulties during childhood was also shown, as per previous reports. Cross-dimensionally, however, neither SCDC nor SDQ-ADHD scores were linked to genetic risk for disorder.

Conclusions: In the general population, genetic aetiologies between social-communication difficulties and ADHD symptoms are shared throughout child and adolescent development and may implicate similar biological pathways that co-vary during development. Within both the ASD and the ADHD dimension, population-based traits are also linked to clinical disorder, although much larger clinical discovery samples are required to reliably detect cross-dimensional trait-disorder relationships.
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http://dx.doi.org/10.1186/s13229-017-0131-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5379648PMC
March 2018

Association between polygenic risk scores for attention-deficit hyperactivity disorder and educational and cognitive outcomes in the general population.

Int J Epidemiol 2017 04;46(2):421-428

Medical Research Centre (MRC) Integrative Epidemiology Unit (IEU) at the University of Bristol, Bristol, UK.

Background: Children with a diagnosis of attention-deficit hyperactivity disorder ADHD) have lower cognitive ability and are at risk of adverse educational outcomes; ADHD genetic risks have been found to predict childhood cognitive ability and other neurodevelopmental traits in the general population; thus genetic risks might plausibly also contribute to cognitive ability later in development and to educational underachievement.

Methods: We generated ADHD polygenic risk scores in the Avon Longitudinal Study of Parents and Children participants (maximum N : 6928 children and 7280 mothers) based on the results of a discovery clinical sample, a genome-wide association study of 727 cases with ADHD diagnosis and 5081 controls. We tested if ADHD polygenic risk scores were associated with educational outcomes and IQ in adolescents and their mothers.

Results: High ADHD polygenic scores in adolescents were associated with worse educational outcomes at Key Stage 3 [national tests conducted at age 13-14 years; β = -1.4 (-2.0 to -0.8), P  = 2.3 × 10 -6 ), at General Certificate of Secondary Education exams at age 15-16 years (β = -4.0 (-6.1 to -1.9), P  = 1.8 × 10 -4 ], reduced odds of sitting Key Stage 5 examinations at age 16-18 years [odds ratio (OR) = 0.90 (0.88 to 0.97), P  = 0.001] and lower IQ scores at age 15.5 [β = -0.8 (-1.2 to -0.4), P  = 2.4 × 10 -4 ]. Moreover, maternal ADHD polygenic scores were associated with lower maternal educational achievement [β = -0.09 (-0.10 to -0.06), P  = 0.005] and lower maternal IQ [β = -0.6 (-1.2 to -0.1), P  = 0.03].

Conclusions: ADHD diagnosis risk alleles impact on functional outcomes in two generations (mother and child) and likely have intergenerational environmental effects.
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http://dx.doi.org/10.1093/ije/dyw216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5424076PMC
April 2017

Implementing the PAIN RelieveIt Randomized Controlled Trial in Hospice Care: Mechanisms for Success and Meeting PCORI Methodology Standards.

West J Nurs Res 2017 07 12;39(7):924-941. Epub 2016 Sep 12.

2 University of Florida, Gainesville, FL, USA.

This purpose of this article is to describe how we adhere to the Patient-Centered Outcomes Research Institute's (PCORI) methodology standards relevant to the design and implementation of our PCORI-funded study, the PAIN RelieveIt Trial. We present details of the PAIN RelieveIt Trial organized by the PCORI methodology standards and components that are relevant to our study. The PAIN RelieveIt Trial adheres to four PCORI standards and 21 subsumed components. The four standards include standards for formulating research questions, standards associated with patient centeredness, standards for data integrity and rigorous analyses, and standards for preventing and handling missing data. In the past 24 months, we screened 2,837 cancer patients and their caregivers; 874 dyads were eligible; 223.5 dyads consented and provided baseline data. Only 55 patients were lost to follow-up-a 25% attrition rate. The design and implementation of the PAIN RelieveIt Trial adhered to PCORI's methodology standards for research rigor.
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http://dx.doi.org/10.1177/0193945916668328DOI Listing
July 2017

Association of Genetic Risk for Schizophrenia With Nonparticipation Over Time in a Population-Based Cohort Study.

Am J Epidemiol 2016 06 10;183(12):1149-58. Epub 2016 May 10.

Progress has recently been made in understanding the genetic basis of schizophrenia and other psychiatric disorders. Longitudinal studies are complicated by participant dropout, which could be related to the presence of psychiatric problems and associated genetic risk. We tested whether common genetic variants implicated in schizophrenia were associated with study nonparticipation among 7,867 children and 7,850 mothers from the Avon Longitudinal Study of Parents and Children (ALSPAC; 1991-2007), a longitudinal population cohort study. Higher polygenic risk scores for schizophrenia were consistently associated with noncompletion of questionnaires by study mothers and children and nonattendance at data collection throughout childhood and adolescence (ages 1-15 years). These associations persisted after adjustment for other potential correlates of nonparticipation. Results suggest that persons at higher genetic risk for schizophrenia are likely to be underrepresented in cohort studies, which will underestimate risk of this and related psychiatric, cognitive, and behavioral phenotypes in the population. Statistical power to detect associations with these phenotypes will be reduced, while analyses of schizophrenia-related phenotypes as outcomes may be biased by the nonrandom missingness of these phenotypes, even if multiple imputation is used. Similarly, in complete-case analyses, collider bias may affect associations between genetic risk and other factors associated with missingness.
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http://dx.doi.org/10.1093/aje/kww009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4908211PMC
June 2016

Parental Origin of Interstitial Duplications at 15q11.2-q13.3 in Schizophrenia and Neurodevelopmental Disorders.

PLoS Genet 2016 05 6;12(5):e1005993. Epub 2016 May 6.

The State Diagnostic and Counselling Centre, Kópavogur, Iceland.

Duplications at 15q11.2-q13.3 overlapping the Prader-Willi/Angelman syndrome (PWS/AS) region have been associated with developmental delay (DD), autism spectrum disorder (ASD) and schizophrenia (SZ). Due to presence of imprinted genes within the region, the parental origin of these duplications may be key to the pathogenicity. Duplications of maternal origin are associated with disease, whereas the pathogenicity of paternal ones is unclear. To clarify the role of maternal and paternal duplications, we conducted the largest and most detailed study to date of parental origin of 15q11.2-q13.3 interstitial duplications in DD, ASD and SZ cohorts. We show, for the first time, that paternal duplications lead to an increased risk of developing DD/ASD/multiple congenital anomalies (MCA), but do not appear to increase risk for SZ. The importance of the epigenetic status of 15q11.2-q13.3 duplications was further underlined by analysis of a number of families, in which the duplication was paternally derived in the mother, who was unaffected, whereas her offspring, who inherited a maternally derived duplication, suffered from psychotic illness. Interestingly, the most consistent clinical characteristics of SZ patients with 15q11.2-q13.3 duplications were learning or developmental problems, found in 76% of carriers. Despite their lower pathogenicity, paternal duplications are less frequent in the general population with a general population prevalence of 0.0033% compared to 0.0069% for maternal duplications. This may be due to lower fecundity of male carriers and differential survival of embryos, something echoed in the findings that both types of duplications are de novo in just over 50% of cases. Isodicentric chromosome 15 (idic15) or interstitial triplications were not observed in SZ patients or in controls. Overall, this study refines the distinct roles of maternal and paternal interstitial duplications at 15q11.2-q13.3, underlining the critical importance of maternally expressed imprinted genes in the contribution of Copy Number Variants (CNVs) at this interval to the incidence of psychotic illness. This work will have tangible benefits for patients with 15q11.2-q13.3 duplications by aiding genetic counseling.
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http://dx.doi.org/10.1371/journal.pgen.1005993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4859484PMC
May 2016