Examining sex-differentiated genetic effects across neuropsychiatric and behavioral traits

Martin, Joanna; Khramtsova, Ekaterina A.; Goleva, Slavina; Blokland, Gabriëlla A.M.; Traglia, Michela; Walters, Raymond; Hübel, Christopher; Coleman, Jonathan R. I.; Breen, Gerome; Børglum, Anders; Demontis, Ditte; Grove, Jakob; Werge, Thomas; Bralten, Janita; Bulik, Cynthia M.; Lee, Phil H.; Mathews, Carol A.; Peterson, Roseann E.; Winham, Stacey J.; Wray, Naomi R.; Edenberg, Howard J.; Guo, Wei; Yao, Yin; Neale, Benjamin M.; Faraone, Stephen V.; Petryshen, Tracey L.; Weiss, Lauren A.; Duncan, Laramie; Goldstein, Jill M.; Smoller, Jordan W.; Stranger, Barbara Elaine; Davis, Lea K.

doi:10.1101/2020.05.04.076042

Cited by 6 publications

(10 citation statements)

References 51 publications

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“…These were 10 predominantly adult-afflicting psychiatric comorbidities for which ICD code definitions had previously been validated. 29 The prevalence of most of these psychiatric comorbidities in the VUMC-EHR was similar to previously reported literature. However, prevalence of these psychiatric comorbidities was much higher in patients with functional seizures, ranging from 2.6% (phobia) to 30.2% (major depressive disorder).…”

Section: Resultssupporting

confidence: 89%

Epidemiology of Functional Seizures Among Adults Treated at a University Hospital

et al. 2020

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IMPORTANCE Functional seizures (formerly psychogenic nonepileptic seizures), paroxysmal episodes that are often similar to epileptic seizures in their clinical presentation and display no aberrant brain electrical patterns, are understudied. Patients experience a long diagnostic delay, few treatment modalities, a high rate of comorbidities, and significant stigma due to the lack of knowledge about functional seizures. OBJECTIVE To characterize the clinical epidemiology of a population of patients with functional seizures observed at Vanderbilt University Medical Center (VUMC). DESIGN, SETTING, AND PARTICIPANTS This case-control study included patients with functional seizures identified in the VUMC electronic health record (VUMC-EHR) system from October 1989 to October 2018. Patients with epilepsy were excluded from the study and all remaining patients in the VUMC medical center system were used as controls. In total, the study included 1431 patients diagnosed with functional seizures, 2251 with epilepsy and functional seizures, 4715 with epilepsy without functional seizures, and 502 200 control patients who received treatment at VUMC for a minimum of a 3 years. Data were analyzed from November 2018 to March 2020. EXPOSURE Diagnosis of functional seizures, as identified from the VUMC-EHR system by an automated phenotyping algorithm that incorporated International Classification of Diseases, Ninth Revision (ICD-9) codes, International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes, Current Procedural Terminology codes, and natural language processing. MAIN OUTCOMES AND MEASURES Associations of functional seizures with comorbidities and risk factors, measured in odds ratios (ORs). RESULTSOf 2 346 808 total patients in the VUMC-EHR aged 18 years or older, 3341 patients with functional seizures were identified (period prevalence, 0.14%), 1062 (74.2%) of whom were women and for which the median (interquartile range) age was 49.3 (39.4-59.9) years. This assessment replicated previously reported associations with psychiatric disorders including posttraumatic stress

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Section: Resultssupporting

confidence: 89%

Epidemiology of Functional Seizures Among Adults Treated at a University Hospital

et al. 2020

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“…Rather, the results indicate that any sex differences in disease signature are likely small and will require additional analyses in larger sample sizes. This notion is further supported by recent work on large-scale genome-wide association studies (GWAS) of schizophrenia (44)(45)(46). These studies did not identify genome-wide significant effect size differences between males and females and the genetic correlation between males and females is statistically not different from 1.0.…”

Section: Discussionmentioning

confidence: 66%

“…These studies did not identify genome-wide significant effect size differences between males and females and the genetic correlation between males and females is statistically not different from 1.0. More broadly, in analyses of large-scale GWAS and biobank data, findings of sex-specific effects or differences in heritability between males and females have been limited (44,46,47). These negative results from otherwise well-powered datasets underscore the challenge of studying the molecular mechanisms underlying clinical differences in schizophrenia between males and females.…”

Section: Discussionmentioning

confidence: 99%

Sex differences in the human brain transcriptome of cases with schizophrenia

Hoffman

Montgomery

et al. 2020

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While schizophrenia differs between males and females in age of onset, symptomatology and the course of the disease, the molecular mechanisms underlying these differences remain uncharacterized. In order to address questions about the sex-specific effects of schizophrenia, we performed a large-scale transcriptome analysis of RNA-seq data from 437 controls and 341 cases from two distinct cohorts from the CommonMind Consortium. Analysis across the cohorts identifies a reproducible gene expression signature of schizophrenia that is highly concordant with previous work. Differential expression across sex is reproducible across cohorts and identifies X- and Y-linked genes, as well as those involved in dosage compensation. Intriguingly, the sex expression signature is also enriched for genes involved in neurexin family protein binding and synaptic organization. Differential expression analysis testing a sex-by-diagnosis interaction effect did not identify any genome-wide signature after multiple testing corrections. Gene coexpression network analysis was performed to reduce dimensionality and elucidate interactions among genes. We found enrichment of co-expression modules for sex-by-diagnosis differential expression signatures, which were highly reproducible across the two cohorts and involve a number of diverse pathways, including neural nucleus development, neuron projection morphogenesis, and regulation of neural precursor cell proliferation. Overall, our results indicate that the effect size of sex differences in schizophrenia gene expression signatures is small and underscore the challenge of identifying robust sex-by-diagnosis signatures, which will require future analyses in larger cohorts.

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“…While this analysis was not significant in the NCMH data, the point estimate was actually higher in the early onset group analysis in NCMH [OR=1.17(0.93–1.47)] compared to PGC [OR=1.08(1.02–1.15)], indicating that the lower power of the smaller NCMH sample to detect such a small effect may have impacted on the lack of consistency in terms of statistical significance. This study also adds to other cross-disorder analyses of common genetic variants, which show moderate genetic correlations across ADHD, anxiety and depression, with no significant sex differences observed across these genetic correlations (11,12).…”

Section: Discussionmentioning

confidence: 70%

“…Genome-wide association studies (GWAS) have identified robustly associated risk alleles for both disorders, accounting for 26% of variance in anxiety and 8.7% of variance in major depressive disorder (MDD) (9,10). The genetic correlation between males and females is very high for each of these disorders and there are no SNPs identified to date showing a genome-wide significant sex difference in allele frequency (11). GWAS have also demonstrated that a significant proportion of the genetic liabilities of anxiety and MDD are shared with other psychiatric disorders in males and females (9–12).…”

Section: Introductionmentioning

confidence: 99%

Examining sex differences in neurodevelopmental and psychiatric genetic risk in anxiety and depression

Martin

Asjadi

Hubbard

et al. 2021

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Anxiety and depression are common mental health disorders and have a higher prevalence in females. They are modestly heritable, share genetic liability with other psychiatric disorders, and are highly heterogeneous. There is evidence that genetic liability to neurodevelopmental disorders, such as attention deficit hyperactivity disorder (ADHD) is associated with anxiety and depression, particularly in females. We investigated sex differences in family history for neurodevelopmental and psychiatric disorders and neurodevelopmental genetic risk burden (indexed by ADHD polygenic risk scores (PRS) and rare copy number variants; CNVs) in individuals with anxiety and depression, also taking into account age at onset. We used two complementary datasets: 1) participants with a self-reported diagnosis of anxiety or depression (N=4,178, 65.5% female; mean age=41.5 years; N=1,315 with genetic data) from the National Centre for Mental Health (NCMH) cohort and 2) a clinical sample of 13,273 (67.6% female; mean age=45.2 years) patients with major depressive disorder (MDD) from the Psychiatric Genomics Consortium (PGC). We tested for sex differences in family history of psychiatric problems and presence of rare CNVs (neurodevelopmental and >500kb loci) in NCMH only and for sex differences in ADHD PRS in both datasets. In the NCMH cohort, females were more likely to report family history of neurodevelopmental and psychiatric disorders, but there were no robust sex differences in ADHD PRS or presence of rare CNVs. There was weak evidence of higher ADHD PRS in females compared to males in the PGC MDD sample, particularly in those with an early onset of MDD. These results do not provide strong evidence of sex differences in neurodevelopmental genetic risk burden in adults with anxiety and depression. This indicates that sex may not be a major index of neurodevelopmental genetic heterogeneity, that is captured by ADHD PRS and rare CNV burden, in adults with anxiety and depression.

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Examining sex-differentiated genetic effects across neuropsychiatric and behavioral traits

Cited by 6 publications

References 51 publications

Epidemiology of Functional Seizures Among Adults Treated at a University Hospital

Epidemiology of Functional Seizures Among Adults Treated at a University Hospital

Sex differences in the human brain transcriptome of cases with schizophrenia

Examining sex differences in neurodevelopmental and psychiatric genetic risk in anxiety and depression

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