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

Martin, Joanna; Walters, Raymond; Demontis, Ditte; Mattheisen, Manuel; Lee, Sang; Robinson, Elise; Brikell, Isabell; Ghirardi, Laura; Larsson, Henrik; Lichtenstein, Paul; Eriksson, Nicholas; Workgroup, iPSYCH–Broad Adhd; Werge, Thomas; Mortensen, Preben Bo; Pedersen, Marianne Giørtz; Mors, Ole; Nordentoft, Merete; Hougaard, David M.; Bybjerg‐Grauholm, Jonas; Wray, Naomi R.; Franke, Barbara; Faraone, Stephen V.; O'Donovan, Michael Conlon; Thapar, Anita; Børglum, Anders D.; Neale, Benjamin M.

doi:10.1016/j.biopsych.2017.11.026

Cited by 152 publications

(97 citation statements)

References 51 publications

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“…4,28 Later-born siblings of girls with ADHD were marginally more likely to receive an ADHD diagnosis than later-born siblings of male probands, echoing recent population-based work. 34 Maternal age interacted with risk status as expected for ADHD outcomes in the ADHD-risk and no-known-risk groups, 35 although not for ASD outcomes. 36 Overall, the variables examined generally did not moderate recurrence risk effects.…”

Section: Discussionmentioning

confidence: 85%

Sibling Recurrence Risk and Cross-aggregation of Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder

et al. 2019

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IMPORTANCE Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are believed to partially share genetic factors and biological influences. As the number of children with these diagnoses rises, so does the number of younger siblings at presumed risk for ADHD and ASD; reliable recurrence risk estimates within and across diagnoses may aid screening and early detection efforts and enhance understanding of potential shared causes. OBJECTIVE To examine within-diagnosis sibling recurrence risk and sibling cross-aggregation of ADHD and ASD among later-born siblings of children with either disorder. DESIGN, SETTING, AND PARTICIPANTS Using data extracted from medical records of 2 large health care systems in the United States, estimates of recurrence risk and cross-aggregation in later-born siblings of children with ADHD or ASD were compared with later-born siblings of children without these diagnoses. One data set included children seen between January 1, 1995, and December 31, 2013; the other included children born between January 1, 1998, and May 17, 2010. Participants included 15 175 later-born siblings of children with ADHD, ASD, and no known diagnosis. The study was conducted from October 2, 2017, to August 14, 2018. MAIN OUTCOMES AND MEASURES Diagnoses of ASD or ADHD in the later-born sibling, ascertained from medical records, were the primary outcomes of interest; moderators included sex, gestational age, and maternal age. RESULTS A total of 15 175 later-born siblings were classified by familial risk status based on the older child’s diagnostic status: ADHD risk (n = 730; male [51.92%]), ASD risk (n = 158; male [48.10%]), and no known risk (n = 14 287; male [50.73%]). Compared with later-born siblings of children without ADHD or ASD, later-born siblings of children with ASD were more likely to be diagnosed with ASD (odds ratio [OR], 30.38; 95% CI, 17.73–52.06) or ADHD in the absence of ASD (OR, 3.70; 95% CI, 1.67–8.21). Compared with later-born siblings of children without a diagnosis, later-born siblings of children with ADHD were more likely to be diagnosed with ADHD (OR, 13.05; 95% CI, 9.86–17.27) or ASD in the absence of ADHD (OR, 4.35; 95% CI, 2.43–7.79). CONCLUSIONS AND RELEVANCE Later-born siblings of children with ASD or ADHD appear to be at elevated risk for the same disorder, but also of being diagnosed with the other disorder. These findings provide further support for shared familial mechanisms underlying ASD and ADHD, which may be useful for genetic and prospective developmental studies. Later-born siblings of children with ADHD or ASD should be monitored for both conditions.

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Section: Discussionmentioning

confidence: 85%

Sibling Recurrence Risk and Cross-aggregation of Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder

et al. 2019

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“…We used mtCOJO to address the genetic relationship between PTSD and other major mental disorders. By applying the most recent PGC GWAS results for 8 mental health traits -autism spectrum disorder, major depression, anorexia nervosa, anxiety (case-control), alcohol dependence, schizophrenia, bipolar disorder, attention deficit hyperactivity disorder (Duncan et al, 2017;Grove et al, 2019;Howard et al, 2019;Martin et al, 2018;Otowa et al, 2016; Schizophrenia Working Group of the Psychiatric Genomics, 2014; Stahl et al, 2019;Walters et al, 2018) -and all the aforementioned traits to our PCL-total quantitative phenotype in EUR, we were able to parse out the genetic signal attributable to PTSD alone. PCL-total remained highly genetically correlated with the unconditioned GWAS when conditioned on genetically correlated psychiatric disorders independently and simultaneously (Figure 7).…”

Section: Disordersmentioning

confidence: 99%

Genomic Characterization of Posttraumatic Stress Disorder in a Large US Military Veteran Sample

Stein

Levey

Cheng

et al. 2019

Preprint

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Individuals vary in their liability to develop Posttraumatic Stress Disorder (PTSD), the symptoms of which are highly heterogeneous, following exposure to life-threatening trauma. Understanding genetic factors that contribute to the biology of PTSD is critical for refining diagnosis and developing new treatments. Using genetic data from more than 250,000 participants in the Million Veteran Program, genomewide association analyses were conducted using a validated electronic health record-based algorithmically-defined PTSD diagnosis phenotype (48,221 cases and 217,223 controls), and PTSD quantitative symptom phenotypes (212,007 individuals). We identified several genome-wide significant loci in the case-control analyses, and numerous such loci in the quantitative trait analyses, including some (e.g., MAD1L1; TCF4; CRHR1) that were associated with multiple symptom sub-domains and total symptom score, and others that were more specific to certain symptom sub-domains (e.g., CAMKV to reexperiencing; SOX6 to hyperarousal). Genetic correlations between all pairs of symptom sub-domains and their total were very high (rg 0.93 -0.98) supporting validity of the PTSD diagnostic construct. We also demonstrate strong shared heritability with a range of traits, show that heritability persists when conditioned on other major psychiatric disorders, present independent replication results, provide support for one of the implicated genes in postmortem brain of individuals with PTSD, and use this information to identify potential drug repositioning candidates. These results point to the utility of genetics to inform and validate the biological coherence of the PTSD syndrome despite considerable heterogeneity at the symptom level, and to provide new directions for treatment development.

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“…Polygenic risk scores were calculated using PRSice 2.0 35 based on genome-wide association summary statistic weights from the largest current GWAS meta-analyses. [36][37][38][39][40] Previous studies have utilized multiple p-value thresholds to create PRS with increasing portions of genomic data to detect changes in R 2 . To minimize the number of exploratory tests, a default a priori p-value threshold of 1.0 was selected using the maximum number of variants available.…”

Section: Polygenic Risk Scoringmentioning

confidence: 99%

Subthreshold psychosis symptoms associated with molecular genetic risk in a population-based cohort: Findings from Generation Scotland

Docherty

Shabalin

Adkins

et al. 2019

Preprint

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Text Word Count: 299/1969 Question: What molecular genetic risks are associated with subthreshold psychosis symptoms in the general population?Findings: In a large population-based cohort (N = 9,084), significant associations of polygenic risks with symptoms were observed. Symptoms were associated with genetic risk for schizophrenia in males, for ADHD and autism spectrum disorder in females, and for neuroticism across both males and females.Meaning: Associations of genetic risk with symptoms in the general population are highly significant and suggest important sex differences.3 Abstract Importance: Subthreshold psychosis symptoms in the general population may be associated with genetic risk for schizophrenia. In this analysis, empirically-derived symptom factor scores led to a detection of significant and robust polygenic signal.Objective: This study sought to optimize genetic association with data-driven symptom factor scores, accounting for cohort factor structure and sex differences.Design: EFA-derived symptom factor scores were regressed onto PRS for schizophrenia in models accounting for age and genetic ancestry principal components. Follow-up examination of symptom factor score associations with other related genetic risks included ADHD, autism, bipolar disorder, major depression, and neuroticism. Participants: This study examined the newly expanded symptom dataset from the Northern European ancestry cohort, Generation Scotland: Scottish Family Health Study (N = 9,105 individuals 18-65 years of age) comprising common variant and subthreshold psychosis symptom data. A total of 5,391 females and 3,713 males with age M[SD] = 45.2 [13] were included in the final analyses. Main Outcome and Measure: Subthreshold psychosis symptoms were measured using the Schizotypal Personality Questionnaire-Brief (SPQ-B). Primary phenotypic factor scores and genome-wide polygenic risk scores (PRS) reflected weighted sum scores and were examined as continuous measures. Polygenic risk scores were calculated from genome-wide association summary statistics using 7,358,674 imputed common genetic variants passing quality control. Results:In males, symptom factor scores were positively associated with polygenic risk for schizophrenia alone and implicated primarily interpersonal/negative symptoms. In females, symptom factor scores were positively associated with polygenic risks for ADHD and autism but not schizophrenia. Scores were robustly associated with genetic risk for neuroticism across both males and females. 4 Conclusions and Relevance:This study detected a significant association of subthreshold psychosis symptoms with genetic risk for schizophrenia and neuroticism in a population-based sample. Furthermore, important sex differences suggest a need for better understanding of schizophrenia risk assessment in females.

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

Cited by 152 publications

References 51 publications

Sibling Recurrence Risk and Cross-aggregation of Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder

Sibling Recurrence Risk and Cross-aggregation of Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder

Genomic Characterization of Posttraumatic Stress Disorder in a Large US Military Veteran Sample

Subthreshold psychosis symptoms associated with molecular genetic risk in a population-based cohort: Findings from Generation Scotland

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