Using common genetic variation to examine phenotypic expression and risk prediction in 22q11.2 deletion syndrome

Robert W. Davies; Ania M. Fiksinski; Elemi J. Breetvelt; Nigel M. Williams; Stephen R. Hooper; Thomas Monfeuga; Anne S. Bassett; Michael J. Owen; Raquel E. Gur; Bernice E. Morrow; Donna M. Mcdonald-Mcginn; Ann Swillen; Eva W. C. Chow; Marianne Van Den Bree; Beverly S. Emanuel; Joris R. Vermeesch; Therese Van Amelsvoort; Celso Arango; Marco Armando; Linda E. Campbell; Joseph F. Cubells; Stephan Eliez; Sixto Garcia-Minaur; Doron Gothelf; Wendy R. Kates; Kieran C. Murphy; Clodagh M. Murphy; Declan G. Murphy; Nicole Philip; Gabriela M. Repetto; Vandana Shashi; Tony J. Simon; Damiàn Heine Suñer; Stefano Vicari; Stephen W. Scherer; Michael P. Epstein; Stephen T. Warren; Sinead Morrison; Samuel Chawner; Claudia Vingerhoets; Jeroen Breckpot; Elfi Vergaelen; Annick Vogels; Stephen Monks; Sarah E. Prasad; Corrado Sandini; Maude Schneider; Johanna Maeder; David Fraguas; Rens Evers; Flora Tassone; Jaume Morey-Canyelles; Opal Y. Ousley; Kevin M. Antshel; Wanda Fremont; Rosemarie Fritsch; Claudia Ornstein; Eileen M. Daly; Gregory A. Costain; Erik Boot; Tracy Heung; T. Blaine Crowley; Elaine H. Zackai; Monica E. Calkins; Ruben C. Gur; Kathryn L. Mccabe; Tiffany Busa; Kelly Schoch; Maria Pontillo; Sasja N. Duijff; René S. Kahn; Michiel Houben; Mariasofia Houben; Leila Kushan; Maria Jalbrzikowski; Miri Carmel; Ehud Mekori-Domachevsky; Elena Michaelovsky; Ronnie Weinberger; Carrie E. Bearden; Jacob A. S. Vorstman

doi:10.1038/s41591-020-1103-1

Using common genetic variation to examine phenotypic expression and risk prediction in 22q11.2 deletion syndrome

Robert W. Davies, Ania M. Fiksinski, Elemi J. Breetvelt, Nigel M. Williams, Stephen R. Hooper, Thomas Monfeuga, Anne S. Bassett, Michael J. Owen, Raquel E. Gur, Bernice E. Morrow, Donna M. Mcdonald-Mcginn, Ann Swillen, Eva W. C. Chow, Marianne Van Den Bree, Beverly S. Emanuel, Joris R. Vermeesch, Therese Van Amelsvoort, Celso Arango, Marco Armando, Linda E. CampbellJoseph F. Cubells, Stephan Eliez, Sixto Garcia-Minaur, Doron Gothelf, Wendy R. Kates, Kieran C. Murphy, Clodagh M. Murphy, Declan G. Murphy, Nicole Philip, Gabriela M. Repetto, Vandana Shashi, Tony J. Simon, Damiàn Heine Suñer, Stefano Vicari, Stephen W. Scherer, Michael P. Epstein, Stephen T. Warren, Sinead Morrison, Samuel Chawner, Claudia Vingerhoets, Jeroen Breckpot, Elfi Vergaelen, Annick Vogels, Stephen Monks, Sarah E. Prasad, Corrado Sandini, Maude Schneider, Johanna Maeder, David Fraguas, Rens Evers, Flora Tassone, Jaume Morey-Canyelles, Opal Y. Ousley, Kevin M. Antshel, Wanda Fremont, Rosemarie Fritsch, Claudia Ornstein, Eileen M. Daly, Gregory A. Costain, Erik Boot, Tracy Heung, T. Blaine Crowley, Elaine H. Zackai, Monica E. Calkins, Ruben C. Gur, Kathryn L. Mccabe, Tiffany Busa, Kelly Schoch, Maria Pontillo, Sasja N. Duijff, René S. Kahn, Michiel Houben, Mariasofia Houben, Leila Kushan, Maria Jalbrzikowski, Miri Carmel, Ehud Mekori-Domachevsky, Elena Michaelovsky, Ronnie Weinberger, Carrie E. Bearden, Jacob A. S. Vorstman^*

^*Autore corrispondente per questo lavoro

Risultato della ricerca: Contributo in rivista › Articolo in rivista

15 Citazioni (Scopus)

Abstract

The 22q11.2 deletion syndrome (22q11DS) is associated with a 20–25% risk of schizophrenia. In a cohort of 962 individuals with 22q11DS, we examined the shared genetic basis between schizophrenia and schizophrenia-related early trajectory phenotypes: sub-threshold symptoms of psychosis, low baseline intellectual functioning and cognitive decline. We studied the association of these phenotypes with two polygenic scores, derived for schizophrenia and intelligence, and evaluated their use for individual risk prediction in 22q11DS. Polygenic scores were not only associated with schizophrenia and baseline intelligence quotient (IQ), respectively, but schizophrenia polygenic score was also significantly associated with cognitive (verbal IQ) decline and nominally associated with sub-threshold psychosis. Furthermore, in comparing the tail-end deciles of the schizophrenia and IQ polygenic score distributions, 33% versus 9% of individuals with 22q11DS had schizophrenia, and 63% versus 24% of individuals had intellectual disability. Collectively, these data show a shared genetic basis for schizophrenia and schizophrenia-related phenotypes and also highlight the future potential of polygenic scores for risk stratification among individuals with highly, but incompletely, penetrant genetic variants.

Lingua originale	English
pagine (da-a)	1912-1918
Numero di pagine	7
Rivista	Nature Medicine
Volume	26
DOI	https://doi.org/10.1038/s41591-020-1103-1
Stato di pubblicazione	Pubblicato - 2020

Keywords

Adolescent
Adult
Aged
Child
Child, Preschool
Cognitive Dysfunction
Cohort Studies
DiGeorge Syndrome
Female
Genetic Variation
Humans
Intellectual Disability
Male
Middle Aged
Multifactorial Inheritance
Phenotype
Risk Factors
Schizophrenia
Young Adult

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10.1038/s41591-020-1103-1

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Davies, R. W., Fiksinski, A. M., Breetvelt, E. J., Williams, N. M., Hooper, S. R., Monfeuga, T., Bassett, A. S., Owen, M. J., Gur, R. E., Morrow, B. E., Mcdonald-Mcginn, D. M., Swillen, A., Chow, E. W. C., Van Den Bree, M., Emanuel, B. S., Vermeesch, J. R., Van Amelsvoort, T., Arango, C., Armando, M., ... Vorstman, J. A. S. (2020). Using common genetic variation to examine phenotypic expression and risk prediction in 22q11.2 deletion syndrome. Nature Medicine, 26, 1912-1918. https://doi.org/10.1038/s41591-020-1103-1

@article{44feb5f9fba54958b790b05628bba493,

title = "Using common genetic variation to examine phenotypic expression and risk prediction in 22q11.2 deletion syndrome",

abstract = "The 22q11.2 deletion syndrome (22q11DS) is associated with a 20–25% risk of schizophrenia. In a cohort of 962 individuals with 22q11DS, we examined the shared genetic basis between schizophrenia and schizophrenia-related early trajectory phenotypes: sub-threshold symptoms of psychosis, low baseline intellectual functioning and cognitive decline. We studied the association of these phenotypes with two polygenic scores, derived for schizophrenia and intelligence, and evaluated their use for individual risk prediction in 22q11DS. Polygenic scores were not only associated with schizophrenia and baseline intelligence quotient (IQ), respectively, but schizophrenia polygenic score was also significantly associated with cognitive (verbal IQ) decline and nominally associated with sub-threshold psychosis. Furthermore, in comparing the tail-end deciles of the schizophrenia and IQ polygenic score distributions, 33% versus 9% of individuals with 22q11DS had schizophrenia, and 63% versus 24% of individuals had intellectual disability. Collectively, these data show a shared genetic basis for schizophrenia and schizophrenia-related phenotypes and also highlight the future potential of polygenic scores for risk stratification among individuals with highly, but incompletely, penetrant genetic variants.",

keywords = "Adolescent, Adult, Aged, Child, Child, Preschool, Cognitive Dysfunction, Cohort Studies, DiGeorge Syndrome, Female, Genetic Variation, Humans, Intellectual Disability, Male, Middle Aged, Multifactorial Inheritance, Phenotype, Risk Factors, Schizophrenia, Young Adult, Adolescent, Adult, Aged, Child, Child, Preschool, Cognitive Dysfunction, Cohort Studies, DiGeorge Syndrome, Female, Genetic Variation, Humans, Intellectual Disability, Male, Middle Aged, Multifactorial Inheritance, Phenotype, Risk Factors, Schizophrenia, Young Adult",

author = "Davies, {Robert W.} and Fiksinski, {Ania M.} and Breetvelt, {Elemi J.} and Williams, {Nigel M.} and Hooper, {Stephen R.} and Thomas Monfeuga and Bassett, {Anne S.} and Owen, {Michael J.} and Gur, {Raquel E.} and Morrow, {Bernice E.} and Mcdonald-Mcginn, {Donna M.} and Ann Swillen and Chow, {Eva W. C.} and {Van Den Bree}, Marianne and Emanuel, {Beverly S.} and Vermeesch, {Joris R.} and {Van Amelsvoort}, Therese and Celso Arango and Marco Armando and Campbell, {Linda E.} and Cubells, {Joseph F.} and Stephan Eliez and Sixto Garcia-Minaur and Doron Gothelf and Kates, {Wendy R.} and Murphy, {Kieran C.} and Murphy, {Clodagh M.} and Murphy, {Declan G.} and Nicole Philip and Repetto, {Gabriela M.} and Vandana Shashi and Simon, {Tony J.} and Su{\~n}er, {Dami{\`a}n Heine} and Stefano Vicari and Scherer, {Stephen W.} and Epstein, {Michael P.} and Warren, {Stephen T.} and Sinead Morrison and Samuel Chawner and Claudia Vingerhoets and Jeroen Breckpot and Elfi Vergaelen and Annick Vogels and Stephen Monks and Prasad, {Sarah E.} and Corrado Sandini and Maude Schneider and Johanna Maeder and David Fraguas and Rens Evers and Flora Tassone and Jaume Morey-Canyelles and Ousley, {Opal Y.} and Antshel, {Kevin M.} and Wanda Fremont and Rosemarie Fritsch and Claudia Ornstein and Daly, {Eileen M.} and Costain, {Gregory A.} and Erik Boot and Tracy Heung and Crowley, {T. Blaine} and Zackai, {Elaine H.} and Calkins, {Monica E.} and Gur, {Ruben C.} and Mccabe, {Kathryn L.} and Tiffany Busa and Kelly Schoch and Maria Pontillo and Duijff, {Sasja N.} and Kahn, {Ren{\'e} S.} and Michiel Houben and Mariasofia Houben and Leila Kushan and Maria Jalbrzikowski and Miri Carmel and Ehud Mekori-Domachevsky and Elena Michaelovsky and Ronnie Weinberger and Bearden, {Carrie E.} and Vorstman, {Jacob A. S.}",

year = "2020",

doi = "10.1038/s41591-020-1103-1",

language = "English",

volume = "26",

pages = "1912--1918",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature America Incorporated:345 Park Avenue South, 6th Floor:New York, NY 10010:(888)331-6288, EMAIL: institutions@natureny.com, INTERNET: http://www.nature.com, Fax: (212)689-9108",

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Davies, RW, Fiksinski, AM, Breetvelt, EJ, Williams, NM, Hooper, SR, Monfeuga, T, Bassett, AS, Owen, MJ, Gur, RE, Morrow, BE, Mcdonald-Mcginn, DM, Swillen, A, Chow, EWC, Van Den Bree, M, Emanuel, BS, Vermeesch, JR, Van Amelsvoort, T, Arango, C, Armando, M, Campbell, LE, Cubells, JF, Eliez, S, Garcia-Minaur, S, Gothelf, D, Kates, WR, Murphy, KC, Murphy, CM, Murphy, DG, Philip, N, Repetto, GM, Shashi, V, Simon, TJ, Suñer, DH, Vicari, S, Scherer, SW, Epstein, MP, Warren, ST, Morrison, S, Chawner, S, Vingerhoets, C, Breckpot, J, Vergaelen, E, Vogels, A, Monks, S, Prasad, SE, Sandini, C, Schneider, M, Maeder, J, Fraguas, D, Evers, R, Tassone, F, Morey-Canyelles, J, Ousley, OY, Antshel, KM, Fremont, W, Fritsch, R, Ornstein, C, Daly, EM, Costain, GA, Boot, E, Heung, T, Crowley, TB, Zackai, EH, Calkins, ME, Gur, RC, Mccabe, KL, Busa, T, Schoch, K, Pontillo, M, Duijff, SN, Kahn, RS, Houben, M, Houben, M, Kushan, L, Jalbrzikowski, M, Carmel, M, Mekori-Domachevsky, E, Michaelovsky, E, Weinberger, R, Bearden, CE & Vorstman, JAS 2020, 'Using common genetic variation to examine phenotypic expression and risk prediction in 22q11.2 deletion syndrome', Nature Medicine, vol. 26, pagg. 1912-1918. https://doi.org/10.1038/s41591-020-1103-1

TY - JOUR

T1 - Using common genetic variation to examine phenotypic expression and risk prediction in 22q11.2 deletion syndrome

AU - Davies, Robert W.

AU - Fiksinski, Ania M.

AU - Breetvelt, Elemi J.

AU - Williams, Nigel M.

AU - Hooper, Stephen R.

AU - Monfeuga, Thomas

AU - Bassett, Anne S.

AU - Owen, Michael J.

AU - Gur, Raquel E.

AU - Morrow, Bernice E.

AU - Mcdonald-Mcginn, Donna M.

AU - Swillen, Ann

AU - Chow, Eva W. C.

AU - Van Den Bree, Marianne

AU - Emanuel, Beverly S.

AU - Vermeesch, Joris R.

AU - Van Amelsvoort, Therese

AU - Arango, Celso

AU - Armando, Marco

AU - Campbell, Linda E.

AU - Cubells, Joseph F.

AU - Eliez, Stephan

AU - Garcia-Minaur, Sixto

AU - Gothelf, Doron

AU - Kates, Wendy R.

AU - Murphy, Kieran C.

AU - Murphy, Clodagh M.

AU - Murphy, Declan G.

AU - Philip, Nicole

AU - Repetto, Gabriela M.

AU - Shashi, Vandana

AU - Simon, Tony J.

AU - Suñer, Damiàn Heine

AU - Vicari, Stefano

AU - Scherer, Stephen W.

AU - Epstein, Michael P.

AU - Warren, Stephen T.

AU - Morrison, Sinead

AU - Chawner, Samuel

AU - Vingerhoets, Claudia

AU - Breckpot, Jeroen

AU - Vergaelen, Elfi

AU - Vogels, Annick

AU - Monks, Stephen

AU - Prasad, Sarah E.

AU - Sandini, Corrado

AU - Schneider, Maude

AU - Maeder, Johanna

AU - Fraguas, David

AU - Evers, Rens

AU - Tassone, Flora

AU - Morey-Canyelles, Jaume

AU - Ousley, Opal Y.

AU - Antshel, Kevin M.

AU - Fremont, Wanda

AU - Fritsch, Rosemarie

AU - Ornstein, Claudia

AU - Daly, Eileen M.

AU - Costain, Gregory A.

AU - Boot, Erik

AU - Heung, Tracy

AU - Crowley, T. Blaine

AU - Zackai, Elaine H.

AU - Calkins, Monica E.

AU - Gur, Ruben C.

AU - Mccabe, Kathryn L.

AU - Busa, Tiffany

AU - Schoch, Kelly

AU - Pontillo, Maria

AU - Duijff, Sasja N.

AU - Kahn, René S.

AU - Houben, Michiel

AU - Houben, Mariasofia

AU - Kushan, Leila

AU - Jalbrzikowski, Maria

AU - Carmel, Miri

AU - Mekori-Domachevsky, Ehud

AU - Michaelovsky, Elena

AU - Weinberger, Ronnie

AU - Bearden, Carrie E.

AU - Vorstman, Jacob A. S.

PY - 2020

Y1 - 2020

N2 - The 22q11.2 deletion syndrome (22q11DS) is associated with a 20–25% risk of schizophrenia. In a cohort of 962 individuals with 22q11DS, we examined the shared genetic basis between schizophrenia and schizophrenia-related early trajectory phenotypes: sub-threshold symptoms of psychosis, low baseline intellectual functioning and cognitive decline. We studied the association of these phenotypes with two polygenic scores, derived for schizophrenia and intelligence, and evaluated their use for individual risk prediction in 22q11DS. Polygenic scores were not only associated with schizophrenia and baseline intelligence quotient (IQ), respectively, but schizophrenia polygenic score was also significantly associated with cognitive (verbal IQ) decline and nominally associated with sub-threshold psychosis. Furthermore, in comparing the tail-end deciles of the schizophrenia and IQ polygenic score distributions, 33% versus 9% of individuals with 22q11DS had schizophrenia, and 63% versus 24% of individuals had intellectual disability. Collectively, these data show a shared genetic basis for schizophrenia and schizophrenia-related phenotypes and also highlight the future potential of polygenic scores for risk stratification among individuals with highly, but incompletely, penetrant genetic variants.

AB - The 22q11.2 deletion syndrome (22q11DS) is associated with a 20–25% risk of schizophrenia. In a cohort of 962 individuals with 22q11DS, we examined the shared genetic basis between schizophrenia and schizophrenia-related early trajectory phenotypes: sub-threshold symptoms of psychosis, low baseline intellectual functioning and cognitive decline. We studied the association of these phenotypes with two polygenic scores, derived for schizophrenia and intelligence, and evaluated their use for individual risk prediction in 22q11DS. Polygenic scores were not only associated with schizophrenia and baseline intelligence quotient (IQ), respectively, but schizophrenia polygenic score was also significantly associated with cognitive (verbal IQ) decline and nominally associated with sub-threshold psychosis. Furthermore, in comparing the tail-end deciles of the schizophrenia and IQ polygenic score distributions, 33% versus 9% of individuals with 22q11DS had schizophrenia, and 63% versus 24% of individuals had intellectual disability. Collectively, these data show a shared genetic basis for schizophrenia and schizophrenia-related phenotypes and also highlight the future potential of polygenic scores for risk stratification among individuals with highly, but incompletely, penetrant genetic variants.

KW - Adolescent

KW - Adult

KW - Aged

KW - Child

KW - Child, Preschool

KW - Cognitive Dysfunction

KW - Cohort Studies

KW - DiGeorge Syndrome

KW - Female

KW - Genetic Variation

KW - Humans

KW - Intellectual Disability

KW - Male

KW - Middle Aged

KW - Multifactorial Inheritance

KW - Phenotype

KW - Risk Factors

KW - Schizophrenia

KW - Young Adult

KW - Adolescent

KW - Adult

KW - Aged

KW - Child

KW - Child, Preschool

KW - Cognitive Dysfunction

KW - Cohort Studies

KW - DiGeorge Syndrome

KW - Female

KW - Genetic Variation

KW - Humans

KW - Intellectual Disability

KW - Male

KW - Middle Aged

KW - Multifactorial Inheritance

KW - Phenotype

KW - Risk Factors

KW - Schizophrenia

KW - Young Adult

UR - http://hdl.handle.net/10807/178817

U2 - 10.1038/s41591-020-1103-1

DO - 10.1038/s41591-020-1103-1

M3 - Article

SN - 1078-8956

VL - 26

SP - 1912

EP - 1918

JO - Nature Medicine

JF - Nature Medicine

ER -

Using common genetic variation to examine phenotypic expression and risk prediction in 22q11.2 deletion syndrome

Abstract

Keywords

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