Population-Based Risk of Psychiatric Disorders Associated With Recurrent Copy Number Variants

Morteza Vaez; Simone Montalbano; Xabier Calle Sánchez; Kajsa-Lotta Georgii Hellberg; Saeid Rasekhi Dehkordi; Morten Dybdahl Krebs; Joeri Meijsen; John Shorter; Jonas Bybjerg-Grauholm; Preben B Mortensen; Anders D Børglum; David M Hougaard; Merete Nordentoft; Daniel H Geschwind; Alfonso Buil; Andrew J Schork; Dorte Helenius; Armin Raznahan; Wesley K Thompson; Thomas Werge; Andrés Ingason; iPSYCH Investigators

doi:10.1001/jamapsychiatry.2024.1453

Population-Based Risk of Psychiatric Disorders Associated With Recurrent Copy Number Variants

Morteza Vaez, Simone Montalbano, Xabier Calle Sánchez, Kajsa-Lotta Georgii Hellberg, Saeid Rasekhi Dehkordi, Morten Dybdahl Krebs, Joeri Meijsen, John Shorter, Jonas Bybjerg-Grauholm, Preben B Mortensen, Anders D Børglum, David M Hougaard, Merete Nordentoft, Daniel H Geschwind, Alfonso Buil, Andrew J Schork, Dorte Helenius, Armin Raznahan, Wesley K Thompson, Thomas WergeAndrés Ingason, iPSYCH Investigators

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

2 Citationer (Scopus)

Abstract

IMPORTANCE: Recurrent copy number variants (rCNVs) have been associated with increased risk of psychiatric disorders in case-control studies, but their population-level impact is unknown.

OBJECTIVE: To provide unbiased population-based estimates of prevalence and risk associated with psychiatric disorders for rCNVs and to compare risks across outcomes, rCNV dosage type (deletions or duplications), and locus features.

DESIGN, SETTING, AND PARTICIPANTS: This genetic association study is an analysis of data from the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) case-cohort sample of individuals born in Denmark in 1981-2008 and followed up until 2015, including (1) all individuals (n = 92 531) with a hospital discharge diagnosis of attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder, major depressive disorder (MDD), or schizophrenia spectrum disorder (SSD) and (2) a subcohort (n = 50 625) randomly drawn from the source population. Data were analyzed from January 2021 to August 2023.

EXPOSURES: Carrier status of deletions and duplications at 27 autosomal rCNV loci was determined from neonatal blood samples genotyped on single-nucleotide variant microarrays.

MAIN OUTCOMES AND MEASURES: Population-based rCNV prevalence was estimated with a survey model using finite population correction to account for oversampling of cases. Hazard ratio (HR) estimates and 95% CIs for psychiatric disorders were derived using weighted Cox proportional hazard models. Risks were compared across outcomes, dosage type, and locus features using generalized estimating equation models.

RESULTS: A total of 3547 rCNVs were identified in 64 735 individuals assigned male at birth (53.8%) and 55 512 individuals assigned female at birth (46.2%) whose age at the end of follow-up ranged from 7.0 to 34.7 years (mean, 21.8 years). Most observed increases in rCNV-associated risk for ADHD, ASD, or SSD were moderate, and risk estimates were highly correlated across these disorders. Notable exceptions included high ASD-associated risk observed for Prader-Willi/Angelman syndrome duplications (HR, 20.8; 95% CI, 7.9-55). No rCNV was associated with increased MDD risk. Also, rCNV-associated risk was positively correlated with locus size and gene constraint but not with dosage type. Comparison with published case-control and community-based studies revealed a higher prevalence of deletions and lower associated increase in risk for several rCNVs in iPSYCH2015.

CONCLUSIONS AND RELEVANCE: This study found that several rCNVs were more prevalent and conferred less risk of psychiatric disorders than estimated previously. Most case-control studies overestimate rCNV-associated risk of psychiatric disorders, likely because of selection bias. In an era where genetics is increasingly being clinically applied, these results highlight the importance of population-based risk estimates for genetics-based predictions.

Originalsprog	Engelsk
Artikelnummer	10
Tidsskrift	JAMA Psychiatry
Vol/bind	81
Nummer	10
Sider (fra-til)	957-966
ISSN	0003-990X
DOI	https://doi.org/10.1001/jamapsychiatry.2024.1453
Status	Udgivet - 1 okt. 2024

Adgang til dokumentet

10.1001/jamapsychiatry.2024.1453

Andre filer og links

Link to publication in Scopus

Citationsformater

Vaez, M., Montalbano, S., Calle Sánchez, X., Georgii Hellberg, K.-L., Dehkordi, S. R., Krebs, M. D., Meijsen, J., Shorter, J., Bybjerg-Grauholm, J., Mortensen, P. B., Børglum, A. D., Hougaard, D. M., Nordentoft, M., Geschwind, D. H., Buil, A., Schork, A. J., Helenius, D., Raznahan, A., Thompson, W. K., ... iPSYCH Investigators (2024). Population-Based Risk of Psychiatric Disorders Associated With Recurrent Copy Number Variants. JAMA Psychiatry, 81(10), 957-966. Artikel 10. https://doi.org/10.1001/jamapsychiatry.2024.1453

@article{117a2b812cdb49c591c69d336172cd1a,

title = "Population-Based Risk of Psychiatric Disorders Associated With Recurrent Copy Number Variants",

abstract = "IMPORTANCE: Recurrent copy number variants (rCNVs) have been associated with increased risk of psychiatric disorders in case-control studies, but their population-level impact is unknown.OBJECTIVE: To provide unbiased population-based estimates of prevalence and risk associated with psychiatric disorders for rCNVs and to compare risks across outcomes, rCNV dosage type (deletions or duplications), and locus features.DESIGN, SETTING, AND PARTICIPANTS: This genetic association study is an analysis of data from the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) case-cohort sample of individuals born in Denmark in 1981-2008 and followed up until 2015, including (1) all individuals (n = 92 531) with a hospital discharge diagnosis of attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder, major depressive disorder (MDD), or schizophrenia spectrum disorder (SSD) and (2) a subcohort (n = 50 625) randomly drawn from the source population. Data were analyzed from January 2021 to August 2023.EXPOSURES: Carrier status of deletions and duplications at 27 autosomal rCNV loci was determined from neonatal blood samples genotyped on single-nucleotide variant microarrays.MAIN OUTCOMES AND MEASURES: Population-based rCNV prevalence was estimated with a survey model using finite population correction to account for oversampling of cases. Hazard ratio (HR) estimates and 95% CIs for psychiatric disorders were derived using weighted Cox proportional hazard models. Risks were compared across outcomes, dosage type, and locus features using generalized estimating equation models.RESULTS: A total of 3547 rCNVs were identified in 64 735 individuals assigned male at birth (53.8%) and 55 512 individuals assigned female at birth (46.2%) whose age at the end of follow-up ranged from 7.0 to 34.7 years (mean, 21.8 years). Most observed increases in rCNV-associated risk for ADHD, ASD, or SSD were moderate, and risk estimates were highly correlated across these disorders. Notable exceptions included high ASD-associated risk observed for Prader-Willi/Angelman syndrome duplications (HR, 20.8; 95% CI, 7.9-55). No rCNV was associated with increased MDD risk. Also, rCNV-associated risk was positively correlated with locus size and gene constraint but not with dosage type. Comparison with published case-control and community-based studies revealed a higher prevalence of deletions and lower associated increase in risk for several rCNVs in iPSYCH2015.CONCLUSIONS AND RELEVANCE: This study found that several rCNVs were more prevalent and conferred less risk of psychiatric disorders than estimated previously. Most case-control studies overestimate rCNV-associated risk of psychiatric disorders, likely because of selection bias. In an era where genetics is increasingly being clinically applied, these results highlight the importance of population-based risk estimates for genetics-based predictions.",

author = "Morteza Vaez and Simone Montalbano and {Calle S{\'a}nchez}, Xabier and {Georgii Hellberg}, Kajsa-Lotta and Dehkordi, {Saeid Rasekhi} and Krebs, {Morten Dybdahl} and Joeri Meijsen and John Shorter and Jonas Bybjerg-Grauholm and Mortensen, {Preben B} and B{\o}rglum, {Anders D} and Hougaard, {David M} and Merete Nordentoft and Geschwind, {Daniel H} and Alfonso Buil and Schork, {Andrew J} and Dorte Helenius and Armin Raznahan and Thompson, {Wesley K} and Thomas Werge and Andr{\'e}s Ingason and {iPSYCH Investigators}",

year = "2024",

month = oct,

day = "1",

doi = "10.1001/jamapsychiatry.2024.1453",

language = "English",

volume = "81",

pages = "957--966",

journal = "JAMA Psychiatry",

issn = "0003-990X",

publisher = "American Medical Association",

number = "10",

}

Vaez, M, Montalbano, S, Calle Sánchez, X, Georgii Hellberg, K-L, Dehkordi, SR, Krebs, MD, Meijsen, J, Shorter, J, Bybjerg-Grauholm, J, Mortensen, PB , Børglum, AD, Hougaard, DM, Nordentoft, M, Geschwind, DH, Buil, A, Schork, AJ, Helenius, D, Raznahan, A, Thompson, WK, Werge, T, Ingason, A & iPSYCH Investigators 2024, 'Population-Based Risk of Psychiatric Disorders Associated With Recurrent Copy Number Variants', JAMA Psychiatry, bind 81, nr. 10, 10, s. 957-966. https://doi.org/10.1001/jamapsychiatry.2024.1453

TY - JOUR

T1 - Population-Based Risk of Psychiatric Disorders Associated With Recurrent Copy Number Variants

AU - Vaez, Morteza

AU - Montalbano, Simone

AU - Calle Sánchez, Xabier

AU - Georgii Hellberg, Kajsa-Lotta

AU - Dehkordi, Saeid Rasekhi

AU - Krebs, Morten Dybdahl

AU - Meijsen, Joeri

AU - Shorter, John

AU - Bybjerg-Grauholm, Jonas

AU - Mortensen, Preben B

AU - Børglum, Anders D

AU - Hougaard, David M

AU - Nordentoft, Merete

AU - Geschwind, Daniel H

AU - Buil, Alfonso

AU - Schork, Andrew J

AU - Helenius, Dorte

AU - Raznahan, Armin

AU - Thompson, Wesley K

AU - Werge, Thomas

AU - Ingason, Andrés

AU - iPSYCH Investigators

PY - 2024/10/1

Y1 - 2024/10/1

N2 - IMPORTANCE: Recurrent copy number variants (rCNVs) have been associated with increased risk of psychiatric disorders in case-control studies, but their population-level impact is unknown.OBJECTIVE: To provide unbiased population-based estimates of prevalence and risk associated with psychiatric disorders for rCNVs and to compare risks across outcomes, rCNV dosage type (deletions or duplications), and locus features.DESIGN, SETTING, AND PARTICIPANTS: This genetic association study is an analysis of data from the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) case-cohort sample of individuals born in Denmark in 1981-2008 and followed up until 2015, including (1) all individuals (n = 92 531) with a hospital discharge diagnosis of attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder, major depressive disorder (MDD), or schizophrenia spectrum disorder (SSD) and (2) a subcohort (n = 50 625) randomly drawn from the source population. Data were analyzed from January 2021 to August 2023.EXPOSURES: Carrier status of deletions and duplications at 27 autosomal rCNV loci was determined from neonatal blood samples genotyped on single-nucleotide variant microarrays.MAIN OUTCOMES AND MEASURES: Population-based rCNV prevalence was estimated with a survey model using finite population correction to account for oversampling of cases. Hazard ratio (HR) estimates and 95% CIs for psychiatric disorders were derived using weighted Cox proportional hazard models. Risks were compared across outcomes, dosage type, and locus features using generalized estimating equation models.RESULTS: A total of 3547 rCNVs were identified in 64 735 individuals assigned male at birth (53.8%) and 55 512 individuals assigned female at birth (46.2%) whose age at the end of follow-up ranged from 7.0 to 34.7 years (mean, 21.8 years). Most observed increases in rCNV-associated risk for ADHD, ASD, or SSD were moderate, and risk estimates were highly correlated across these disorders. Notable exceptions included high ASD-associated risk observed for Prader-Willi/Angelman syndrome duplications (HR, 20.8; 95% CI, 7.9-55). No rCNV was associated with increased MDD risk. Also, rCNV-associated risk was positively correlated with locus size and gene constraint but not with dosage type. Comparison with published case-control and community-based studies revealed a higher prevalence of deletions and lower associated increase in risk for several rCNVs in iPSYCH2015.CONCLUSIONS AND RELEVANCE: This study found that several rCNVs were more prevalent and conferred less risk of psychiatric disorders than estimated previously. Most case-control studies overestimate rCNV-associated risk of psychiatric disorders, likely because of selection bias. In an era where genetics is increasingly being clinically applied, these results highlight the importance of population-based risk estimates for genetics-based predictions.

AB - IMPORTANCE: Recurrent copy number variants (rCNVs) have been associated with increased risk of psychiatric disorders in case-control studies, but their population-level impact is unknown.OBJECTIVE: To provide unbiased population-based estimates of prevalence and risk associated with psychiatric disorders for rCNVs and to compare risks across outcomes, rCNV dosage type (deletions or duplications), and locus features.DESIGN, SETTING, AND PARTICIPANTS: This genetic association study is an analysis of data from the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) case-cohort sample of individuals born in Denmark in 1981-2008 and followed up until 2015, including (1) all individuals (n = 92 531) with a hospital discharge diagnosis of attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder, major depressive disorder (MDD), or schizophrenia spectrum disorder (SSD) and (2) a subcohort (n = 50 625) randomly drawn from the source population. Data were analyzed from January 2021 to August 2023.EXPOSURES: Carrier status of deletions and duplications at 27 autosomal rCNV loci was determined from neonatal blood samples genotyped on single-nucleotide variant microarrays.MAIN OUTCOMES AND MEASURES: Population-based rCNV prevalence was estimated with a survey model using finite population correction to account for oversampling of cases. Hazard ratio (HR) estimates and 95% CIs for psychiatric disorders were derived using weighted Cox proportional hazard models. Risks were compared across outcomes, dosage type, and locus features using generalized estimating equation models.RESULTS: A total of 3547 rCNVs were identified in 64 735 individuals assigned male at birth (53.8%) and 55 512 individuals assigned female at birth (46.2%) whose age at the end of follow-up ranged from 7.0 to 34.7 years (mean, 21.8 years). Most observed increases in rCNV-associated risk for ADHD, ASD, or SSD were moderate, and risk estimates were highly correlated across these disorders. Notable exceptions included high ASD-associated risk observed for Prader-Willi/Angelman syndrome duplications (HR, 20.8; 95% CI, 7.9-55). No rCNV was associated with increased MDD risk. Also, rCNV-associated risk was positively correlated with locus size and gene constraint but not with dosage type. Comparison with published case-control and community-based studies revealed a higher prevalence of deletions and lower associated increase in risk for several rCNVs in iPSYCH2015.CONCLUSIONS AND RELEVANCE: This study found that several rCNVs were more prevalent and conferred less risk of psychiatric disorders than estimated previously. Most case-control studies overestimate rCNV-associated risk of psychiatric disorders, likely because of selection bias. In an era where genetics is increasingly being clinically applied, these results highlight the importance of population-based risk estimates for genetics-based predictions.

UR - http://www.scopus.com/inward/record.url?scp=85201007809&partnerID=8YFLogxK

U2 - 10.1001/jamapsychiatry.2024.1453

DO - 10.1001/jamapsychiatry.2024.1453

M3 - Journal article

C2 - 38922630

SN - 0003-990X

VL - 81

SP - 957

EP - 966

JO - JAMA Psychiatry

JF - JAMA Psychiatry

IS - 10

M1 - 10

ER -

Population-Based Risk of Psychiatric Disorders Associated With Recurrent Copy Number Variants

Abstract

Adgang til dokumentet

Andre filer og links

Fingeraftryk

Citationsformater