Prevalence of rearrangements in the 22q11.2 region and population-based risk of neuropsychiatric and developmental disorders in a Danish population: a case-cohort study

Line Olsen; Thomas Sparsø; Shantel M. Weinsheimer; Marcelo Bertalan Quintanilha Dos Santos; Wiktor Mazin; Anders Rosengren; Xabier Calle Sanchez; Louise K. Hoeffding; Henriette Schmock; Marie Baekvad-Hansen; Jonas Bybjerg-Grauholm; Mark J. Daly; Benjamin M. Neale; Marianne G. Pedersen; Esben Agerbo; Ole Mors; Anders Børglum; Merete Nordentoft; David M. Hougaard; Preben Bo Mortensen; Daniel H. Geschwind; Carsten Pedersen; Wesley K. Thompson; Thomas Werge

doi:10.1016/S2215-0366(18)30168-8

Prevalence of rearrangements in the 22q11.2 region and population-based risk of neuropsychiatric and developmental disorders in a Danish population: a case-cohort study

Line Olsen, Thomas Sparsø, Shantel M. Weinsheimer, Marcelo Bertalan Quintanilha Dos Santos, Wiktor Mazin, Anders Rosengren, Xabier Calle Sanchez, Louise K. Hoeffding, Henriette Schmock, Marie Baekvad-Hansen, Jonas Bybjerg-Grauholm, Mark J. Daly, Benjamin M. Neale, Marianne G. Pedersen, Esben Agerbo, Ole Mors, Anders Børglum, Merete Nordentoft, David M. Hougaard, Preben Bo MortensenDaniel H. Geschwind, Carsten Pedersen, Wesley K. Thompson, Thomas Werge^*

^*Corresponding author for this work

Department of Clinical Medicine

35 Citations (Scopus)

Abstract

Background: Although the pathogenic nature of copy number variants (CNVs) on chromosome 22q11.2 has been recognised for decades, unbiased estimates of their population prevalence, mortality, disease risks, and diagnostic trajectories are absent. We aimed to provide the true population prevalence of 22q11.2 CNVs and associated trajectory of disease risk and mortality by use of the unbiased, representative Danish iPSYCH population case cohort. Methods: This case-cohort study was done on a population of 86 189 individuals selected from the iPSYCH case cohort of 1 472 762 singletons born in Denmark between May 1, 1981, and Dec 31, 2005, who have a known mother from the Danish Civil Registration System, were residents in Denmark at 1 year of age, and enrolled in the iPSYCH Initiative. We used epidemiological methods in conjunction with nationwide hospital registers to analyse the iPSYCH case cohort of individuals with attention-deficit hyperactivity disorder (ADHD), major depressive disorder, schizophrenia, autism, or bipolar disorder and a random population-based sample. The main outcomes assessed were the population prevalence of 22q11.2 rearrangements, and associated unbiased, population-adjusted estimates and 31-year disease risk trajectories for major neuropsychiatric disorders. Findings: Population prevalence in the Danish population was one in 3672 (seven of 25 704 [0·027%; 95% CI 0·012–0·057]) for deletions and one in 1606 (17 of 25 704 [0·066%; 0·040–0·107]) for duplications. Mortality after the age of 1 year among carriers was zero, and hazard ratios for neuropsychiatric disorders ranged from 2·60 to 82·44 for both rearrangements. By the age of 32 years, about 10% of individuals with deletions or duplications had developed ADHD, autism, or intellectual disability, and deletion carriers had higher probability than duplication carriers of co-occurring intellectual disability or epilepsy. Interpretation: The significantly different prevalence of 22q11.2 duplications and deletions indicates distinct selective pressures on these rearrangements. Although risk of congenital abnormalities, developmental delay, and intellectual disability is elevated in deletion carriers, the overall prevalence of neuropsychiatric disorders is higher in duplication carriers, which implies that identification and clinical monitoring should extend beyond congenital traits and into child and adolescent psychiatry. Funding: Capital Region's Research Foundation for Mental Health Research, The Lundbeck Foundation, and US National Institutes of Health.

Original language	English
Journal	The Lancet Psychiatry
Volume	5
Issue number	7
Pages (from-to)	573-580
Number of pages	8
ISSN	2215-0366
DOIs	https://doi.org/10.1016/S2215-0366(18)30168-8
Publication status	Published - 2018

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10.1016/S2215-0366(18)30168-8

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Olsen, L., Sparsø, T., Weinsheimer, S. M., Dos Santos, M. B. Q., Mazin, W., Rosengren, A., Sanchez, X. C., Hoeffding, L. K., Schmock, H., Baekvad-Hansen, M., Bybjerg-Grauholm, J., Daly, M. J., Neale, B. M., Pedersen, M. G., Agerbo, E., Mors, O., Børglum, A., Nordentoft, M., Hougaard, D. M., ... Werge, T. (2018). Prevalence of rearrangements in the 22q11.2 region and population-based risk of neuropsychiatric and developmental disorders in a Danish population: a case-cohort study. The Lancet Psychiatry, 5(7), 573-580. https://doi.org/10.1016/S2215-0366(18)30168-8

Prevalence of rearrangements in the 22q11.2 region and population-based risk of neuropsychiatric and developmental disorders in a Danish population : a case-cohort study. / Olsen, Line; Sparsø, Thomas; Weinsheimer, Shantel M. et al.

In: The Lancet Psychiatry, Vol. 5, No. 7, 2018, p. 573-580.

Research output: Contribution to journal › Journal article › Research › peer-review

Olsen, L, Sparsø, T, Weinsheimer, SM, Dos Santos, MBQ, Mazin, W, Rosengren, A, Sanchez, XC, Hoeffding, LK, Schmock, H, Baekvad-Hansen, M, Bybjerg-Grauholm, J, Daly, MJ, Neale, BM, Pedersen, MG, Agerbo, E, Mors, O, Børglum, A, Nordentoft, M, Hougaard, DM, Mortensen, PB, Geschwind, DH, Pedersen, C, Thompson, WK & Werge, T 2018, 'Prevalence of rearrangements in the 22q11.2 region and population-based risk of neuropsychiatric and developmental disorders in a Danish population: a case-cohort study', The Lancet Psychiatry, vol. 5, no. 7, pp. 573-580. https://doi.org/10.1016/S2215-0366(18)30168-8

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title = "Prevalence of rearrangements in the 22q11.2 region and population-based risk of neuropsychiatric and developmental disorders in a Danish population: a case-cohort study",

abstract = "Background: Although the pathogenic nature of copy number variants (CNVs) on chromosome 22q11.2 has been recognised for decades, unbiased estimates of their population prevalence, mortality, disease risks, and diagnostic trajectories are absent. We aimed to provide the true population prevalence of 22q11.2 CNVs and associated trajectory of disease risk and mortality by use of the unbiased, representative Danish iPSYCH population case cohort. Methods: This case-cohort study was done on a population of 86 189 individuals selected from the iPSYCH case cohort of 1 472 762 singletons born in Denmark between May 1, 1981, and Dec 31, 2005, who have a known mother from the Danish Civil Registration System, were residents in Denmark at 1 year of age, and enrolled in the iPSYCH Initiative. We used epidemiological methods in conjunction with nationwide hospital registers to analyse the iPSYCH case cohort of individuals with attention-deficit hyperactivity disorder (ADHD), major depressive disorder, schizophrenia, autism, or bipolar disorder and a random population-based sample. The main outcomes assessed were the population prevalence of 22q11.2 rearrangements, and associated unbiased, population-adjusted estimates and 31-year disease risk trajectories for major neuropsychiatric disorders. Findings: Population prevalence in the Danish population was one in 3672 (seven of 25 704 [0·027%; 95% CI 0·012–0·057]) for deletions and one in 1606 (17 of 25 704 [0·066%; 0·040–0·107]) for duplications. Mortality after the age of 1 year among carriers was zero, and hazard ratios for neuropsychiatric disorders ranged from 2·60 to 82·44 for both rearrangements. By the age of 32 years, about 10% of individuals with deletions or duplications had developed ADHD, autism, or intellectual disability, and deletion carriers had higher probability than duplication carriers of co-occurring intellectual disability or epilepsy. Interpretation: The significantly different prevalence of 22q11.2 duplications and deletions indicates distinct selective pressures on these rearrangements. Although risk of congenital abnormalities, developmental delay, and intellectual disability is elevated in deletion carriers, the overall prevalence of neuropsychiatric disorders is higher in duplication carriers, which implies that identification and clinical monitoring should extend beyond congenital traits and into child and adolescent psychiatry. Funding: Capital Region's Research Foundation for Mental Health Research, The Lundbeck Foundation, and US National Institutes of Health.",

author = "Line Olsen and Thomas Spars{\o} and Weinsheimer, {Shantel M.} and {Dos Santos}, {Marcelo Bertalan Quintanilha} and Wiktor Mazin and Anders Rosengren and Sanchez, {Xabier Calle} and Hoeffding, {Louise K.} and Henriette Schmock and Marie Baekvad-Hansen and Jonas Bybjerg-Grauholm and Daly, {Mark J.} and Neale, {Benjamin M.} and Pedersen, {Marianne G.} and Esben Agerbo and Ole Mors and Anders B{\o}rglum and Merete Nordentoft and Hougaard, {David M.} and Mortensen, {Preben Bo} and Geschwind, {Daniel H.} and Carsten Pedersen and Thompson, {Wesley K.} and Thomas Werge",

year = "2018",

doi = "10.1016/S2215-0366(18)30168-8",

language = "English",

volume = "5",

pages = "573--580",

journal = "The Lancet Psychiatry",

issn = "2215-0366",

publisher = "TheLancet Publishing Group",

number = "7",

}

TY - JOUR

T1 - Prevalence of rearrangements in the 22q11.2 region and population-based risk of neuropsychiatric and developmental disorders in a Danish population

T2 - a case-cohort study

AU - Olsen, Line

AU - Sparsø, Thomas

AU - Weinsheimer, Shantel M.

AU - Dos Santos, Marcelo Bertalan Quintanilha

AU - Mazin, Wiktor

AU - Rosengren, Anders

AU - Sanchez, Xabier Calle

AU - Hoeffding, Louise K.

AU - Schmock, Henriette

AU - Baekvad-Hansen, Marie

AU - Bybjerg-Grauholm, Jonas

AU - Daly, Mark J.

AU - Neale, Benjamin M.

AU - Pedersen, Marianne G.

AU - Agerbo, Esben

AU - Mors, Ole

AU - Børglum, Anders

AU - Nordentoft, Merete

AU - Hougaard, David M.

AU - Mortensen, Preben Bo

AU - Geschwind, Daniel H.

AU - Pedersen, Carsten

AU - Thompson, Wesley K.

AU - Werge, Thomas

PY - 2018

Y1 - 2018

N2 - Background: Although the pathogenic nature of copy number variants (CNVs) on chromosome 22q11.2 has been recognised for decades, unbiased estimates of their population prevalence, mortality, disease risks, and diagnostic trajectories are absent. We aimed to provide the true population prevalence of 22q11.2 CNVs and associated trajectory of disease risk and mortality by use of the unbiased, representative Danish iPSYCH population case cohort. Methods: This case-cohort study was done on a population of 86 189 individuals selected from the iPSYCH case cohort of 1 472 762 singletons born in Denmark between May 1, 1981, and Dec 31, 2005, who have a known mother from the Danish Civil Registration System, were residents in Denmark at 1 year of age, and enrolled in the iPSYCH Initiative. We used epidemiological methods in conjunction with nationwide hospital registers to analyse the iPSYCH case cohort of individuals with attention-deficit hyperactivity disorder (ADHD), major depressive disorder, schizophrenia, autism, or bipolar disorder and a random population-based sample. The main outcomes assessed were the population prevalence of 22q11.2 rearrangements, and associated unbiased, population-adjusted estimates and 31-year disease risk trajectories for major neuropsychiatric disorders. Findings: Population prevalence in the Danish population was one in 3672 (seven of 25 704 [0·027%; 95% CI 0·012–0·057]) for deletions and one in 1606 (17 of 25 704 [0·066%; 0·040–0·107]) for duplications. Mortality after the age of 1 year among carriers was zero, and hazard ratios for neuropsychiatric disorders ranged from 2·60 to 82·44 for both rearrangements. By the age of 32 years, about 10% of individuals with deletions or duplications had developed ADHD, autism, or intellectual disability, and deletion carriers had higher probability than duplication carriers of co-occurring intellectual disability or epilepsy. Interpretation: The significantly different prevalence of 22q11.2 duplications and deletions indicates distinct selective pressures on these rearrangements. Although risk of congenital abnormalities, developmental delay, and intellectual disability is elevated in deletion carriers, the overall prevalence of neuropsychiatric disorders is higher in duplication carriers, which implies that identification and clinical monitoring should extend beyond congenital traits and into child and adolescent psychiatry. Funding: Capital Region's Research Foundation for Mental Health Research, The Lundbeck Foundation, and US National Institutes of Health.

AB - Background: Although the pathogenic nature of copy number variants (CNVs) on chromosome 22q11.2 has been recognised for decades, unbiased estimates of their population prevalence, mortality, disease risks, and diagnostic trajectories are absent. We aimed to provide the true population prevalence of 22q11.2 CNVs and associated trajectory of disease risk and mortality by use of the unbiased, representative Danish iPSYCH population case cohort. Methods: This case-cohort study was done on a population of 86 189 individuals selected from the iPSYCH case cohort of 1 472 762 singletons born in Denmark between May 1, 1981, and Dec 31, 2005, who have a known mother from the Danish Civil Registration System, were residents in Denmark at 1 year of age, and enrolled in the iPSYCH Initiative. We used epidemiological methods in conjunction with nationwide hospital registers to analyse the iPSYCH case cohort of individuals with attention-deficit hyperactivity disorder (ADHD), major depressive disorder, schizophrenia, autism, or bipolar disorder and a random population-based sample. The main outcomes assessed were the population prevalence of 22q11.2 rearrangements, and associated unbiased, population-adjusted estimates and 31-year disease risk trajectories for major neuropsychiatric disorders. Findings: Population prevalence in the Danish population was one in 3672 (seven of 25 704 [0·027%; 95% CI 0·012–0·057]) for deletions and one in 1606 (17 of 25 704 [0·066%; 0·040–0·107]) for duplications. Mortality after the age of 1 year among carriers was zero, and hazard ratios for neuropsychiatric disorders ranged from 2·60 to 82·44 for both rearrangements. By the age of 32 years, about 10% of individuals with deletions or duplications had developed ADHD, autism, or intellectual disability, and deletion carriers had higher probability than duplication carriers of co-occurring intellectual disability or epilepsy. Interpretation: The significantly different prevalence of 22q11.2 duplications and deletions indicates distinct selective pressures on these rearrangements. Although risk of congenital abnormalities, developmental delay, and intellectual disability is elevated in deletion carriers, the overall prevalence of neuropsychiatric disorders is higher in duplication carriers, which implies that identification and clinical monitoring should extend beyond congenital traits and into child and adolescent psychiatry. Funding: Capital Region's Research Foundation for Mental Health Research, The Lundbeck Foundation, and US National Institutes of Health.

U2 - 10.1016/S2215-0366(18)30168-8

DO - 10.1016/S2215-0366(18)30168-8

M3 - Journal article

C2 - 29886042

AN - SCOPUS:85048542431

SN - 2215-0366

VL - 5

SP - 573

EP - 580

JO - The Lancet Psychiatry

JF - The Lancet Psychiatry

IS - 7

ER -

Prevalence of rearrangements in the 22q11.2 region and population-based risk of neuropsychiatric and developmental disorders in a Danish population: a case-cohort study

Abstract

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