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 -
