Polygenic and developmental profiles of autism differ by age at diagnosis

X Xinhe Zhang J Jakob Grove Y Yuanjun Gu C Cornelia K. Buus L Lea K. Nielsen S Sharon A. S. Neufeld M Mahmoud Koko D Daniel S. Malawsky E Emma M. Wade E Ellen Verhoef A Anna Gui L Laura Hegemann C Carrie Allison A Alex Tsompanidis D Deep Adhya R Rosemary Holt O Omar Al-Rubaie R Ramin Ali Marandi Ghoddousi A Alexander E. P. Heazell J Jonathan Mill A Alice Franklin R Rosie Bamford M Matthew E. Hurles M Mahmoud Mousa D David H. Rowitch K Kathy K. Niakan G Graham J. Burton T Tereza Cindrova-Davies D Deepak P. Srivastava L Lucia Dutan-Polit A Adam Pavlinek L Laura Sichlinger R Roland Nagy M Madeline A. Lancaster J Jose Gonzalez-Martinez T Tal Biron-Shental L Lidia V. Gabis D Dorothea Floris R Richard Bethlehem M Michael V. Lombardo M Marcin Radecki M Meng-Chuan Lai Y Yeshaya David Greenberg E Elizabeth Weir F Florina Uzefovsky Y Yumnah T. Khan J Juan Pablo Del Rio D David M. Hougaard P Preben Bo Mortensen M Merete Nordentoft T Thomas Werge C Caroline M. Nievergelt A Adam X. Maihofer E Elizabeth G. Atkinson C Chia-Yen Chen K Karmel W. Choi J Jonathan R. I. Coleman N Nikolaos P. Daskalakis L Laramie E. Duncan R Renato Polimanti C Cindy Aaronson A Ananda B. Amstadter S Soren B. Andersen O Ole A. Andreassen P Paul A. Arbisi A Allison E. Ashley-Koch S S. Bryn Austin E Esmina Avdibegoviç D Dragan Babić S Silviu-Alin Bacanu D Dewleen G. Baker A Anthony Batzler J Jean C. Beckham S Sintia Belangero C Corina Benjet C Carisa Bergner L Linda M. Bierer J Joanna M. Biernacka L Laura J. Bierut J Jonathan I. Bisson M Marco P. Boks E Elizabeth A. Bolger A Amber Brandolino G Gerome Breen R Rodrigo Affonseca Bressan R Richard A. Bryant A Angela C. Bustamante J Jonas Bybjerg-Grauholm M Marie Bækvad-Hansen S Sigrid Børte L Leah Cahn J Joseph R. Calabrese J Jose Miguel Caldas-de-Almeida C Chris Chatzinakos S Sheraz Cheema S Sean A. P. Clouston L Lucia Colodro-Conde B Brandon J. Coombes C Carlos S. Cruz-Fuentes A Anders M. Dale S Shareefa Dalvie L Lea K. Davis J Jürgen Deckert D Douglas L. Delahanty M Michelle F. Dennis F Frank Desarnaud C Christopher P. DiPietro S Seth G. Disner A Anna R. Docherty K Katharina Domschke G Grete Dyb A Alma Džubur Kulenović H Howard J. Edenberg A Alexandra Evans C Chiara Fabbri N Negar Fani L Lindsay A. Farrer A Adriana Feder N Norah C. Feeny J Janine D. Flory D David Forbes C Carol E. Franz S Sandro Galea M Melanie E. Garrett B Bizu Gelaye J Joel Gelernter E Elbert Geuze C Charles F. Gillespie S Slavina B. Goleva S Scott D. Gordon A Aferdita Goçi L Lana Ruvolo Grasser C Camila Guindalini M Magali Haas S Saskia Hagenaars M Michael A. Hauser A Andrew C. Heath S Sian M. J. Hemmings V Victor Hesselbrock I Ian B. Hickie K Kelleigh Hogan D David Michael Hougaard H Hailiang Huang L Laura M. Huckins K Kristian Hveem M Miro Jakovljević A Arash Javanbakht G Gregory D. Jenkins J Jessica Johnson I Ian Jones T Tanja Jovanovic K Karen-Inge Karstoft M Milissa L. Kaufman J James L. Kennedy R Ronald C. Kessler A Alaptagin Khan N Nathan A. Kimbrel A Anthony P. King N Nastassja Koen R Roman Kotov H Henry R. Kranzler K Kristi Krebs W William S. Kremen P Pei-Fen Kuan B Bruce R. Lawford L Lauren A. M. Lebois K Kelli Lehto D Daniel F. Levey C Catrin Lewis I Israel Liberzon S Sarah D. Linnstaedt M Mark W. Logue A Adriana Lori Y Yi Lu B Benjamin J. Luft M Michelle K. Lupton J Jurjen J. Luykx I Iouri Makotkine J Jessica L. Maples-Keller S Shelby Marchese C Charles Marmar N Nicholas G. Martin G Gabriela A. Martínez-Levy K Kerrie McAloney A Alexander McFarlane K Katie A. McLaughlin S Samuel A. McLean S Sarah E. Medland D Divya Mehta J Jacquelyn Meyers V Vasiliki Michopoulos E Elizabeth A. Mikita L Lili Milani W William Milberg M Mark W. Miller R Rajendra A. Morey C Charles Phillip Morris O Ole Mors M Mary S. Mufford E Elliot C. Nelson S Sonya B. Norman N Nicole R. Nugent M Meaghan O’Donnell H Holly K. Orcutt P Pedro M. Pan M Matthew S. Panizzon G Gita A. Pathak E Edward S. Peters A Alan L. Peterson M Matthew Peverill R Robert H. Pietrzak M Melissa A. Polusny B Bernice Porjesz A Abigail Powers X Xue-Jun Qin A Andrew Ratanatharathorn V Victoria B. Risbrough A Andrea L. Roberts A Alex O. Rothbaum B Barbara O. Rothbaum P Peter Roy-Byrne K Kenneth J. Ruggiero A Ariane Rung H Heiko Runz B Bart P. F. Rutten S Stacey Saenz de Viteri G Giovanni Abrahão Salum L Laura Sampson S Sixto E. Sanchez M Marcos Santoro C Carina Seah S Soraya Seedat J Julia S. Seng A Andrey Shabalin C Christina M. Sheerin D Derrick Silove A Alicia K. Smith J Jordan W. Smoller S Scott R. Sponheim D Dan J. Stein S Synne Stensland J Jennifer S. Stevens J Jennifer A. Sumner M Martin H. Teicher W Wesley K. Thompson A Arun K. Tiwari E Edward Trapido M Monica Uddin R Robert J. Ursano U Unnur Valdimarsdóttir M Miranda Van Hooff E Eric Vermetten C Christiaan H. Vinkers J Joanne Voisey Y Yunpeng Wang Z Zhewu Wang M Monika Waszczuk H Heike Weber F Frank R. Wendt M Michelle A. Williams D Douglas E. Williamson B Bendik S. Winsvold S Sherry Winternitz C Christiane Wolf E Erika J. Wolf Y Yan Xia Y Ying Xiong R Rachel Yehuda K Keith A. Young R Ross McD. Young C Clement C. Zai G Gwyneth C. Zai M Mark Zervas H Hongyu Zhao L Lori A. Zoellner J John-Anker Zwart T Terri deRoon-Cassini S Sanne J. H. van Rooij L Leigh L. van den Heuvel M Murray B. Stein K Kerry J. Ressler K Karestan C. Koenen D Daniel H. Geschwind N Naomi R. Wray A Alexandra Havdahl A Angelica Ronald B Beate St Pourcain E Elise B. Robinson T Thomas Bourgeron S Simon Baron-Cohen A Anders D. Børglum H Hilary C. Martin V Varun Warrier

Abstract

Abstract Although autism has historically been conceptualized as a condition that emerges in early childhood 1,2 , many autistic people are diagnosed later in life 3–5 . It is unknown whether earlier- and later-diagnosed autism have different developmental trajectories and genetic profiles. Using longitudinal data from four independent birth cohorts, we demonstrate that two different socioemotional and behavioural trajectories are associated with age at diagnosis. In independent cohorts of autistic individuals, common genetic variants account for approximately 11% of the variance in age at autism diagnosis, similar to the contribution of individual sociodemographic and clinical factors, which typically explain less than 15% of this variance. We further demonstrate that the polygenic architecture of autism can be broken down into two modestly genetically correlated ( r g  = 0.38, s.e. = 0.07) autism polygenic factors. One of these factors is associated with earlier autism diagnosis and lower social and communication abilities in early childhood, but is only moderately genetically correlated with attention deficit–hyperactivity disorder (ADHD) and mental-health conditions. Conversely, the second factor is associated with later autism diagnosis and increased socioemotional and behavioural difficulties in adolescence, and has moderate to high positive genetic correlations with ADHD and mental-health conditions. These findings indicate that earlier- and later-diagnosed autism have different developmental trajectories and genetic profiles. Our findings have important implications for how we conceptualize autism and provide a model to explain some of the diversity found in autism.

Article Details

Journal Nature
Volume / Issue Vol. 646, Issue 8087
Published October 30, 2025
Pages 1146-1155
ISSN 0028-0836
Publisher Nature Portfolio

Journal Info

Nature

Nature Portfolio

ISSN: 0028-0836 Health Sciences

Authors (293)

X

Xinhe Zhang

J

Jakob Grove

Y

Yuanjun Gu

C

Cornelia K. Buus

L

Lea K. Nielsen

S

Sharon A. S. Neufeld

M

Mahmoud Koko

D

Daniel S. Malawsky

E

Emma M. Wade

E

Ellen Verhoef

A

Anna Gui

L

Laura Hegemann

C

Carrie Allison

A

Alex Tsompanidis

D

Deep Adhya

R

Rosemary Holt

O

Omar Al-Rubaie

R

Ramin Ali Marandi Ghoddousi

A

Alexander E. P. Heazell

J

Jonathan Mill

A

Alice Franklin

R

Rosie Bamford

M

Matthew E. Hurles

M

Mahmoud Mousa

D

David H. Rowitch

K

Kathy K. Niakan

G

Graham J. Burton

T

Tereza Cindrova-Davies

D

Deepak P. Srivastava

L

Lucia Dutan-Polit

A

Adam Pavlinek

L

Laura Sichlinger

R

Roland Nagy

M

Madeline A. Lancaster

J

Jose Gonzalez-Martinez

T

Tal Biron-Shental

L

Lidia V. Gabis

D

Dorothea Floris

R

Richard Bethlehem

M

Michael V. Lombardo

M

Marcin Radecki

M

Meng-Chuan Lai

Y

Yeshaya David Greenberg

E

Elizabeth Weir

F

Florina Uzefovsky

Y

Yumnah T. Khan

J

Juan Pablo Del Rio

D

David M. Hougaard

P

Preben Bo Mortensen

M

Merete Nordentoft

T

Thomas Werge

C

Caroline M. Nievergelt

A

Adam X. Maihofer

E

Elizabeth G. Atkinson

C

Chia-Yen Chen

K

Karmel W. Choi

J

Jonathan R. I. Coleman

N

Nikolaos P. Daskalakis

L

Laramie E. Duncan

R

Renato Polimanti

C

Cindy Aaronson

A

Ananda B. Amstadter

S

Soren B. Andersen

O

Ole A. Andreassen

P

Paul A. Arbisi

A

Allison E. Ashley-Koch

S

S. Bryn Austin

E

Esmina Avdibegoviç

D

Dragan Babić

S

Silviu-Alin Bacanu

D

Dewleen G. Baker

A

Anthony Batzler

J

Jean C. Beckham

S

Sintia Belangero

C

Corina Benjet

C

Carisa Bergner

L

Linda M. Bierer

J

Joanna M. Biernacka

L

Laura J. Bierut

J

Jonathan I. Bisson

M

Marco P. Boks

E

Elizabeth A. Bolger

A

Amber Brandolino

G

Gerome Breen

R

Rodrigo Affonseca Bressan

R

Richard A. Bryant

A

Angela C. Bustamante

J

Jonas Bybjerg-Grauholm

M

Marie Bækvad-Hansen

S

Sigrid Børte

L

Leah Cahn

J

Joseph R. Calabrese

J

Jose Miguel Caldas-de-Almeida

C

Chris Chatzinakos

S

Sheraz Cheema

S

Sean A. P. Clouston

L

Lucia Colodro-Conde

B

Brandon J. Coombes

C

Carlos S. Cruz-Fuentes

A

Anders M. Dale

S

Shareefa Dalvie

L

Lea K. Davis

J

Jürgen Deckert

D

Douglas L. Delahanty

M

Michelle F. Dennis

F

Frank Desarnaud

C

Christopher P. DiPietro

S

Seth G. Disner

A

Anna R. Docherty

K

Katharina Domschke

G

Grete Dyb

A

Alma Džubur Kulenović

H

Howard J. Edenberg

A

Alexandra Evans

C

Chiara Fabbri

N

Negar Fani

L

Lindsay A. Farrer

A

Adriana Feder

N

Norah C. Feeny

J

Janine D. Flory

D

David Forbes

C

Carol E. Franz

S

Sandro Galea

M

Melanie E. Garrett

B

Bizu Gelaye

J

Joel Gelernter

E

Elbert Geuze

C

Charles F. Gillespie

S

Slavina B. Goleva

S

Scott D. Gordon

A

Aferdita Goçi

L

Lana Ruvolo Grasser

C

Camila Guindalini

M

Magali Haas

S

Saskia Hagenaars

M

Michael A. Hauser

A

Andrew C. Heath

S

Sian M. J. Hemmings

V

Victor Hesselbrock

I

Ian B. Hickie

K

Kelleigh Hogan

D

David Michael Hougaard

H

Hailiang Huang

L

Laura M. Huckins

K

Kristian Hveem

M

Miro Jakovljević

A

Arash Javanbakht

G

Gregory D. Jenkins

J

Jessica Johnson

I

Ian Jones

T

Tanja Jovanovic

K

Karen-Inge Karstoft

M

Milissa L. Kaufman

J

James L. Kennedy

R

Ronald C. Kessler

A

Alaptagin Khan

N

Nathan A. Kimbrel

A

Anthony P. King

N

Nastassja Koen

R

Roman Kotov

H

Henry R. Kranzler

K

Kristi Krebs

W

William S. Kremen

P

Pei-Fen Kuan

B

Bruce R. Lawford

L

Lauren A. M. Lebois

K

Kelli Lehto

D

Daniel F. Levey

C

Catrin Lewis

I

Israel Liberzon

S

Sarah D. Linnstaedt

M

Mark W. Logue

A

Adriana Lori

Y

Yi Lu

B

Benjamin J. Luft

M

Michelle K. Lupton

J

Jurjen J. Luykx

I

Iouri Makotkine

J

Jessica L. Maples-Keller

S

Shelby Marchese

C

Charles Marmar

N

Nicholas G. Martin

G

Gabriela A. Martínez-Levy

K

Kerrie McAloney

A

Alexander McFarlane

K

Katie A. McLaughlin

S

Samuel A. McLean

S

Sarah E. Medland

D

Divya Mehta

J

Jacquelyn Meyers

V

Vasiliki Michopoulos

E

Elizabeth A. Mikita

L

Lili Milani

W

William Milberg

M

Mark W. Miller

R

Rajendra A. Morey

C

Charles Phillip Morris

O

Ole Mors

M

Mary S. Mufford

E

Elliot C. Nelson

S

Sonya B. Norman

N

Nicole R. Nugent

M

Meaghan O’Donnell

H

Holly K. Orcutt

P

Pedro M. Pan

M

Matthew S. Panizzon

G

Gita A. Pathak

E

Edward S. Peters

A

Alan L. Peterson

M

Matthew Peverill

R

Robert H. Pietrzak

M

Melissa A. Polusny

B

Bernice Porjesz

A

Abigail Powers

X

Xue-Jun Qin

A

Andrew Ratanatharathorn

V

Victoria B. Risbrough

A

Andrea L. Roberts

A

Alex O. Rothbaum

B

Barbara O. Rothbaum

P

Peter Roy-Byrne

K

Kenneth J. Ruggiero

A

Ariane Rung

H

Heiko Runz

B

Bart P. F. Rutten

S

Stacey Saenz de Viteri

G

Giovanni Abrahão Salum

L

Laura Sampson

S

Sixto E. Sanchez

M

Marcos Santoro

C

Carina Seah

S

Soraya Seedat

J

Julia S. Seng

A

Andrey Shabalin

C

Christina M. Sheerin

D

Derrick Silove

A

Alicia K. Smith

J

Jordan W. Smoller

S

Scott R. Sponheim

D

Dan J. Stein

S

Synne Stensland

J

Jennifer S. Stevens

J

Jennifer A. Sumner

M

Martin H. Teicher

W

Wesley K. Thompson

A

Arun K. Tiwari

E

Edward Trapido

M

Monica Uddin

R

Robert J. Ursano

U

Unnur Valdimarsdóttir

M

Miranda Van Hooff

E

Eric Vermetten

C

Christiaan H. Vinkers

J

Joanne Voisey

Y

Yunpeng Wang

Z

Zhewu Wang

M

Monika Waszczuk

H

Heike Weber

F

Frank R. Wendt

M

Michelle A. Williams

D

Douglas E. Williamson

B

Bendik S. Winsvold

S

Sherry Winternitz

C

Christiane Wolf

E

Erika J. Wolf

Y

Yan Xia

Y

Ying Xiong

R

Rachel Yehuda

K

Keith A. Young

R

Ross McD. Young

C

Clement C. Zai

G

Gwyneth C. Zai

M

Mark Zervas

H

Hongyu Zhao

L

Lori A. Zoellner

J

John-Anker Zwart

T

Terri deRoon-Cassini

S

Sanne J. H. van Rooij

L

Leigh L. van den Heuvel

M

Murray B. Stein

K

Kerry J. Ressler

K

Karestan C. Koenen

D

Daniel H. Geschwind

N

Naomi R. Wray

A

Alexandra Havdahl

A

Angelica Ronald

B

Beate St Pourcain

E

Elise B. Robinson

T

Thomas Bourgeron

S

Simon Baron-Cohen

A

Anders D. Børglum

H

Hilary C. Martin

V

Varun Warrier