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:10.1016/j.biopsych.2020.12.024

Cited by 59 publications

(66 citation statements)

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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 [ 12 , 14 ].…”

Section: Discussionmentioning

confidence: 83%

“…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) [ 10 , 11 ]. The genetic correlation between males and females is very high for each of these disorders and larger samples are needed to identify SNPs showing a genome-wide significant sex difference in allele frequency [ 12 , 13 ]. 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 [ 10 – 12 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

“…The genetic correlation between males and females is very high for each of these disorders and larger samples are needed to identify SNPs showing a genome-wide significant sex difference in allele frequency [ 12 , 13 ]. 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 [ 10 – 12 , 14 ]. As such, considering sex-specific genetic effects that are shared across disorders is a complementary approach to primary genetic studies that examine sex differences in anxiety and depression.…”

Section: Introductionmentioning

confidence: 99%

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

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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Section: Discussionmentioning

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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“…In the present study, the association between the PRS and worse cognitive performance in mid- and old age, as well as worse school performance was seen in males only with no trend effects in females, indicating sex-specific effects of schizophrenia genetics on cognitive ability in healthy individuals across the entire lifespan. Although it has been proposed that the impact of sex should be tested in genetic studies of schizophrenia given the significant differences in disease manifestation 56–58 , to our knowledge, sex differences in the effect of schizophrenia PRS on cognition has only been considered in one previous study, where sex-stratified analyses showed that the effect of schizophrenia PRS on verbal memory and semantic fluency in older adults reached significance only in males 40 . Here, we were able to demonstrate a significant sex*PRS interaction thus demonstrating that there are statistically reliable differences in the effect of PRS between the sexes, and showed that this effect was not seen for a genetic score for general cognitive ability, but instead specific to schizophrenia genetics.…”

Section: Discussionmentioning

confidence: 99%

“…A schizophrenia GWAS stratified by sex did not reveal any genome-wide significant sex-specific associations 59 , but a genome-wide genotype-by-sex interaction analysis of risk for schizophrenia found genome-wide significant SNP-by-sex interactions 57 . However, no consistent sex differences in SNP-based heritability have been identified in schizophrenia 58 . Taken together, our results suggest that the effect of schizophrenia genetics on a certain disease endophenotype, cognitive ability, is sex-specific.…”

Section: Discussionmentioning

confidence: 99%

Sex-specific effects of polygenic risk for schizophrenia on lifespan cognitive functioning in healthy individuals

Koch

Nyberg

Lundquist

et al. 2021

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Polygenic risk for schizophrenia has been associated with lower cognitive ability and age-related cognitive change in healthy individuals. Despite well-established neuropsychological sex differences in schizophrenia patients, genetic studies on sex differences in schizophrenia in relation to cognitive phenotypes are scarce. Here, we investigated whether the effect of a polygenic risk score (PRS) for schizophrenia on childhood, midlife and late life cognitive function in healthy individuals is modified by sex, and if PRS is linked to accelerated cognitive decline. Using a longitudinal data set from healthy individuals aged 25-100 years (N = 1,459) spanning a 25-year period, we found that PRS was associated with lower cognitive ability (episodic memory, semantic memory, visuospatial ability), but not with accelerated cognitive decline. A significant interaction effect between sex and PRS was seen on cognitive task performance, and sex-stratified analyses showed that the effect of PRS was male-specific. In a sub-sample, we observed a male-specific effect of the PRS on school performance at age 12 (N = 496). Our findings of sex-specific effects of schizophrenia genetics on cognitive functioning across the life-span indicate that the effects of underlying disease genetics on cognitive functioning is dependent on biological processes that differ between the sexes.

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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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Examining Sex-Differentiated Genetic Effects Across Neuropsychiatric and Behavioral Traits

Cited by 59 publications

References 53 publications

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

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

Sex-specific effects of polygenic risk for schizophrenia on lifespan cognitive functioning in healthy individuals

Epidemiology of Functional Seizures Among Adults Treated at a University Hospital

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