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Article ; Online: The impact of assortative mating, participation bias and socioeconomic status on the polygenic risk of behavioural and psychiatric traits.

Cabrera-Mendoza, Brenda / Wendt, Frank R / Pathak, Gita A / Yengo, Loic / Polimanti, Renato

Nature human behaviour

2024

Abstract: To investigate assortative mating (AM), participation bias and socioeconomic status (SES) with respect to the genetics of behavioural and psychiatric traits, we estimated AM signatures using gametic phase disequilibrium and within-spouses and within- ... ...

Abstract	To investigate assortative mating (AM), participation bias and socioeconomic status (SES) with respect to the genetics of behavioural and psychiatric traits, we estimated AM signatures using gametic phase disequilibrium and within-spouses and within-siblings polygenic risk score correlation analyses, also performing a SES conditional analysis. The cross-method meta-analysis identified AM genetic signatures for multiple alcohol-related phenotypes, bipolar disorder, major depressive disorder, schizophrenia and Tourette syndrome. Here, after SES conditioning, we observed changes in the AM genetic signatures for maximum habitual alcohol intake, frequency of drinking alcohol and Tourette syndrome. We also observed significant gametic phase disequilibrium differences between UK Biobank mental health questionnaire responders versus non-responders for major depressive disorder and alcohol use disorder. These results highlight the impact of AM, participation bias and SES on the polygenic risk of behavioural and psychiatric traits, particularly in alcohol-related traits.
Language	English
Publishing date	2024-02-16
Publishing country	England
Document type	Journal Article
ISSN	2397-3374
ISSN (online)	2397-3374
DOI	10.1038/s41562-024-01828-5
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Article ; Online: Unraveling COVID-19 relationship with anxiety disorders and symptoms using genome-wide data.

Asgel, Zeynep / Kouakou, Manuela R / Koller, Dora / Pathak, Gita A / Cabrera-Mendoza, Brenda / Polimanti, Renato

Journal of affective disorders

2024 Volume 352, Page(s) 333–341

Abstract: Background: There is still a limited understanding of the dynamics contributing to the comorbidity of COVID-19 and anxiety outcomes.: Methods: To dissect the pleiotropic mechanisms contributing to COVID-19/anxiety comorbidity, we used genome-wide ... ...

Abstract	Background: There is still a limited understanding of the dynamics contributing to the comorbidity of COVID-19 and anxiety outcomes. Methods: To dissect the pleiotropic mechanisms contributing to COVID-19/anxiety comorbidity, we used genome-wide data from UK Biobank (up to 420,531 participants), FinnGen Project (up to 329,077 participants), Million Veteran Program (175,163 participants), and COVID-19 Host Genetics Initiative (up to 122,616 cases and 2,475,240 controls). Specifically, we assessed global and local genetic correlation and genetically inferred effects linking COVID-19 outcomes (infection, hospitalization, and severe respiratory symptoms) to anxiety disorders and symptoms. Results: We observed a strong genetic correlation of anxiety disorder with COVID-19 positive status (rg = 0.35, p = 2×10 Conclusions: This study provided insights into the pleiotropic mechanisms linking COVID-19 and anxiety outcomes, suggesting differences between dynamics related to anxiety disorders and those related to anxiety symptoms.
MeSH term(s)	Humans ; COVID-19 ; Anxiety Disorders/epidemiology ; Anxiety Disorders/genetics ; Anxiety/epidemiology ; Anxiety/genetics ; Pain ; Ethanol ; Genome-Wide Association Study
Chemical Substances	Ethanol (3K9958V90M)
Language	English
Publishing date	2024-02-19
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	135449-8
ISSN	1573-2517 ; 0165-0327
ISSN (online)	1573-2517
ISSN	0165-0327
DOI	10.1016/j.jad.2024.02.061
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Article: Household income does not affect the pleiotropy of schizophrenia genetic liability with mental and physical health outcomes.

Kouakou, Manuela R / Cabrera-Mendoza, Brenda / Pathak, Gita A / Cannon, Tyrone D / Polimanti, Renato

medRxiv : the preprint server for health sciences

2023

Abstract: Background and hypothesis: Individuals with schizophrenia (SCZ) suffer from comorbidities that substantially reduce their life expectancy. Socioeconomic inequalities could contribute to many of the negative health outcomes associated with SCZ.: Study ... ...

Abstract	Background and hypothesis: Individuals with schizophrenia (SCZ) suffer from comorbidities that substantially reduce their life expectancy. Socioeconomic inequalities could contribute to many of the negative health outcomes associated with SCZ. Study design: We investigated genome-wide datasets related to SCZ (52,017 cases and 75,889 controls) from the Psychiatric Genomics Consortium, household income (HI; N=361,687) from UK Biobank, and 2,202 medical endpoints assessed in up to 342,499 FinnGen participants. A phenome-wide genetic correlation analysis of SCZ and HI was performed, also assessing whether SCZ genetic correlations were influenced by HI effect on SCZ. Additionally, SCZ and HI direct effects on medical endpoints were estimated using multivariable Mendelian randomization (MR). Study results: SCZ and HI showed overlapping genetic correlations with 70 traits (p<2.89×10 Conclusions: The effect of SCZ genetic liability on mental and physical health may not be strongly affected by socioeconomic differences. This suggests that SCZ-specific strategies are needed to reduce negative health outcomes affecting patients and high-risk individuals.
Language	English
Publishing date	2023-09-26
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.09.25.23296085
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Article ; Online: Estimating the direct effects of the genetic liabilities to bipolar disorder, schizophrenia, and behavioral traits on suicide attempt using a multivariable Mendelian randomization approach.

Cabrera-Mendoza, Brenda / Aydin, Necla / Fries, Gabriel R / Docherty, Anna R / Walss-Bass, Consuelo / Polimanti, Renato

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

2024

Abstract: Bipolar disorder (BD) and schizophrenia (SZ) are associated with higher odds of suicide attempt (SA). In this study, we aimed to explore the effect of BD and SZ genetic liabilities on SA, also considering the contribution of behavioral traits, ... ...

Abstract	Bipolar disorder (BD) and schizophrenia (SZ) are associated with higher odds of suicide attempt (SA). In this study, we aimed to explore the effect of BD and SZ genetic liabilities on SA, also considering the contribution of behavioral traits, socioeconomic factors, and substance use disorders. Leveraging large-scale genome-wide association data from the Psychiatric Genomics Consortium (PGC) and the UK Biobank (UKB), we conducted a two-sample Mendelian randomization (MR) analysis to evaluate the putative causal effect of BD (41,917 cases, 371,549 controls) and SZ (53,386 cases, 77,258 controls) on SA (26,590 cases, 492,022 controls). Then, we assessed the putative causal effect of BD and SZ on behavioral traits, socioeconomic factors, and substance use disorders. Considering the associations identified, we evaluated the direct causal effect of behavioral traits, socioeconomic factors, and substance use disorders on SA using a multivariable MR approach. The genetic liabilities to BD and SZ were associated with higher odds of SA (BD odds ratio (OR) = 1.24, p = 3.88 × 10
Language	English
Publishing date	2024-02-23
Publishing country	England
Document type	Journal Article
ZDB-ID	639471-1
ISSN	1740-634X ; 0893-133X
ISSN (online)	1740-634X
ISSN	0893-133X
DOI	10.1038/s41386-024-01833-2
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Article: Unraveling COVID-19 Relationship with Anxiety Disorders and Symptoms.

Asgel, Zeynep / Kouakou, Manuela R / Koller, Dora / Pathak, Gita A / Cabrera-Mendoza, Brenda / Polimanti, Renato

medRxiv : the preprint server for health sciences

2023

Abstract: Background: While COVID-19 outcomes are associated with increased anxiety, individuals affected by anxiety disorders are more likely to develop severe COVID-19 outcomes.: Methods: We used genome-wide data from UK Biobank (up to 420,531 participants), ...

Abstract	Background: While COVID-19 outcomes are associated with increased anxiety, individuals affected by anxiety disorders are more likely to develop severe COVID-19 outcomes. Methods: We used genome-wide data from UK Biobank (up to 420,531 participants), FinnGen Project (up to 329,077 participants), Million Veteran Program (175,163 participants), and COVID-19 Host Genetics Initiative (up to 122,616 cases and 2,475,240 controls) to investigate possible causal effects and shared genetic mechanisms linking COVID-19 outcomes to anxiety disorders and symptoms. Results: We observed a strong genetic correlation of anxiety disorder with COVID-19 positive status (rg=0.35, p=2 × 10 Conclusions: This study provided important insights into the relationship between COVID-19 and mental health, differentiating the dynamics linking anxiety disorders to COVID-19 from the effect of COVID-19 on anxiety symptoms.
Language	English
Publishing date	2023-07-23
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.07.21.23293001
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Article: Brain-Wide Mendelian Randomization Study of Anxiety Disorders and Symptoms.

Zanoaga, Mihaela-Diana / Friligkou, Eleni / He, Jun / Pathak, Gita A / Koller, Dora / Cabrera-Mendoza, Brenda / Stein, Murray B / Polimanti, Renato

medRxiv : the preprint server for health sciences

2023

Abstract: Background: To gain insights into the role of brain structure and function on anxiety (ANX), we conducted a genetically informed investigation leveraging information from ANX genome-wide association studies available from UK Biobank (UKB; N=380,379), ... ...

Abstract	Background: To gain insights into the role of brain structure and function on anxiety (ANX), we conducted a genetically informed investigation leveraging information from ANX genome-wide association studies available from UK Biobank (UKB; N=380,379), FinnGen Program (N=290,361), and Million Veteran Program (MVP; N=199,611) together with UKB genome-wide data (N=33,224) related to 3,935 brain imaging-derived phenotypes (IDP). Methods: A genetic correlation analysis between ANX and brain IDPs was performed using linkage disequilibrium score regression. To investigate ANX-brain associations, a two-sample Mendelian randomization (MR) was performed considering multiple methods and sensitivity analyses. A subsequent multivariable MR (MVMR) was executed to distinguish between direct and indirect effects. Finally, a generalized linear model was used to explore the associations of brain IDPs with ANX symptoms. Results: After false discovery rate correction (FDR q<0.05), we identified 41 brain IDPs genetically correlated with ANX without heterogeneity among the datasets investigated (i.e., UKB, FinnGen, and MVP). Six of these IDPs showed genetically inferred causal effects on ANX. In the subsequent MVMR analysis, reduced area of the right posterior middle-cingulate gyrus (rpMCG; beta=-0.09, P= 8.01×10 Conclusions: This study identified genetically inferred effects generalizable across large cohorts, contributing to understand how changes in brain structure and function can lead to ANX.
Language	English
Publishing date	2023-09-13
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.09.12.23295448
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Article: Estimating the direct effects of the genetic liabilities to bipolar disorder, schizophrenia, and behavioral traits on suicide attempt using a multivariable Mendelian randomization approach.

Cabrera-Mendoza, Brenda / Aydin, Necla / Fries, Gabriel R / Docherty, Anna R / Walss-Bass, Consuelo / Polimanti, Renato

medRxiv : the preprint server for health sciences

2023

Abstract	Bipolar disorder (BD) and schizophrenia (SZ) are associated with higher odds of suicide attempt (SA). In this study, we aimed to explore the effect of BD and SZ genetic liabilities on SA, also considering the contribution of behavioral traits, socioeconomic factors, and substance use disorders. Leveraging large-scale genome-wide association data from the Psychiatric Genomics Consortium (PGC) and the UK Biobank (UKB), we conducted a two-sample Mendelian randomization (MR) analysis to evaluate the putative causal effect of BD (41,917 cases, 371,549 controls) and SZ (53,386 cases, 77,258 controls) on SA (26,590 cases, 492,022 controls). Then, we assessed the putative causal effect of BD and SZ on behavioral traits, socioeconomic factors, and substance use disorders. Considering the associations identified, we evaluated the direct causal effect of behavioral traits, socioeconomic factors, and substance use disorders on SA using a multivariable MR approach. The genetic liabilities to BD and SZ were associated with higher odds of SA (BD odds ratio (OR)=1.24, p=3.88×10
Language	English
Publishing date	2023-08-16
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.08.14.23294083
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Article ; Online: Brainwide Mendelian Randomization Study of Anxiety Disorders and Symptoms.

Zanoaga, Mihaela-Diana / Friligkou, Eleni / He, Jun / Pathak, Gita A / Koller, Dora / Cabrera-Mendoza, Brenda / Stein, Murray B / Polimanti, Renato

Biological psychiatry

2023 Volume 95, Issue 8, Page(s) 810–817

Abstract	Background: To gain insights into the role of brain structure and function on anxiety (ANX), we conducted a genetically informed investigation leveraging information from ANX genome-wide association studies available from the UK Biobank (n = 380,379), the FinnGen Program (n = 290,361), and the Million Veteran Program (n = 175,163) together with UK Biobank genome-wide data (n = 33,224) related to 3935 brain imaging-derived phenotypes (IDPs). Methods: A genetic correlation analysis between ANX and brain IDPs was performed using linkage disequilibrium score regression. To investigate ANX-brain associations, a 2-sample Mendelian randomization was performed considering multiple methods and sensitivity analyses. A subsequent multivariable Mendelian randomization was conducted to distinguish between direct and indirect effects. Finally, a generalized linear model was used to explore the associations of brain IDPs with ANX symptoms. Results: After false discovery rate correction (q < .05), we identified 41 brain IDPs genetically correlated with ANX without heterogeneity among the datasets investigated (i.e., UK Biobank, FinnGen, and Million Veteran Program). Six of these IDPs showed genetically inferred causal effects on ANX. In the subsequent multivariable Mendelian randomization analysis, reduced area of the right posterior middle cingulate gyrus (β = -0.09, p = 8.01 × 10 Conclusions: This study identified genetically inferred effects that are generalizable across large cohorts, thereby contributing to our understanding of how changes in brain structure and function can lead to ANX.
MeSH term(s)	Humans ; Genome-Wide Association Study ; Mendelian Randomization Analysis ; Anxiety Disorders/genetics ; Anxiety/genetics ; Brain/diagnostic imaging ; Polymorphism, Single Nucleotide
Language	English
Publishing date	2023-11-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	209434-4
ISSN	1873-2402 ; 0006-3223
ISSN (online)	1873-2402
ISSN	0006-3223
DOI	10.1016/j.biopsych.2023.11.006
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Article ; Online: Sex differences in the pleiotropy of hearing difficulty with imaging-derived phenotypes: a brain-wide investigation.

He, Jun / Cabrera-Mendoza, Brenda / De Angelis, Flavio / Pathak, Gita A / Koller, Dora / Curhan, Sharon G / Curhan, Gary C / Mecca, Adam P / van Dyck, Christopher H / Polimanti, Renato

Brain : a journal of neurology

2024

Abstract: Hearing difficulty (HD) is one of the major health burdens in older adults. While aging-related changes in the peripheral auditory system play an important role, genetic variation associated with brain structure and function could also be involved in HD ... ...

Abstract	Hearing difficulty (HD) is one of the major health burdens in older adults. While aging-related changes in the peripheral auditory system play an important role, genetic variation associated with brain structure and function could also be involved in HD predisposition. We analyzed a large-scale HD genome-wide association study (GWAS; Ntotal = 501,825, 56% females) and GWAS data related to 3,935 brain imaging-derived phenotypes (IDPs) assessed in up to 33,224 individuals (52% females) using multiple magnetic resonance imaging modalities. To investigate HD pleiotropy with brain structure and function, we conducted genetic correlation, latent causal variable, Mendelian randomization, and multivariable generalized linear regression analyses. Additionally, we performed local genetic correlation and multi-trait colocalization analyses to identify genomic regions and loci implicated in the pleiotropic mechanisms shared between HD and brain IDPs. We observed a widespread genetic correlation of HD with 120 IDPs in females, 89 IDPs in males, and 171 IDPs in the sex-combined analysis. The latent causal variable analysis showed that some of these genetic correlations could be due to cause-effect relationships. For seven correlations, the causal effects were also confirmed by the Mendelian randomization approach: vessel volume→HD in the sex-combined analysis; hippocampus volume→HD, cerebellum grey matter volume→HD, primary visual cortex volume→HD, and HD→fluctuation amplitudes of node 46 in resting-state functional MRI dimensionality 100 in females; global mean thickness→HD and HD→mean orientation dispersion index in superior corona radiata in males. The local genetic correlation analysis identified 13 pleiotropic regions between HD and these seven IDPs. We also observed a colocalization signal for the rs13026575 variant between HD, primary visual cortex volume, and SPTBN1 transcriptomic regulation in females. Brain structure and function may have a role in the sex differences in HD predisposition via possible cause-effect relationships and shared regulatory mechanisms.
Language	English
Publishing date	2024-03-08
Publishing country	England
Document type	Journal Article
ZDB-ID	80072-7
ISSN	1460-2156 ; 0006-8950
ISSN (online)	1460-2156
ISSN	0006-8950
DOI	10.1093/brain/awae077
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Article ; Online: Correction: Psychosocial moderators of polygenic risk scores of inflammatory biomarkers in relation to GrimAge.

Tamman, Amanda J F / Koller, Dora / Nagamatsu, Sheila / Cabrera-Mendoza, Brenda / Abdallah, Chadi / Krystal, John H / Gelernter, Joel / Montalvo-Ortiz, Janitza L / Polimanti, Renato / Pietrzak, Robert H

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

2024 Volume 49, Issue 4, Page(s) 764

Language	English
Publishing date	2024-01-05
Publishing country	England
Document type	Published Erratum
ZDB-ID	639471-1
ISSN	1740-634X ; 0893-133X
ISSN (online)	1740-634X
ISSN	0893-133X
DOI	10.1038/s41386-023-01786-y
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