ARTICLE OPEN
Hypo hesis-d i en genome-wide associa ion s udies p o ide
no el insigh s in o gene ics o eading disabili ies
Kai lyn M. P ice
1,2,3
, Ka en G. Wigg
1
, Else Eising
4
, Yu Feng
1
, Ki s en Blokland
2
, Ma ga e Wilkinson
2
, Elizabe h N. Ke
5,6
,
Sha on L. Guge
5
, Quan i a i e T ai Wo king G oup o he GenLang Conso ium*, Simon E. Fishe
4,7
, Mau een W. Lo e
2,6
,
Lisa J. S ug
8,9
and Ca hy L. Ba
1,2,3
✉
© The Au ho (s) 2022
Reading Disabili y (RD) is o en cha ac e ized by di ficul ies in he phonology o he language. While he molecula mechanisms
unde lying i a e la gely unde e mined, loci a e being e ealed by genome-wide associa ion s udies (GWAS). In a p e ious GWAS o
wo d eading (P ice, 2020), we obse ed ha op single-nucleo ide polymo phisms (SNPs) we e loca ed nea o o in genes in ol ed
in neu onal mig a ion/axon guidance (NM/AG) o loci implica ed in au ism spec um diso de (ASD). A p ominen heo y o RD
e iology posi s ha i in ol es dis u bed neu onal mig a ion, while po en ial links be ween RD-ASD ha e no been ex ensi ely
in es iga ed. To imp o e powe o iden i y associa ed loci, we up-weigh ed a ian s in ol ed in NM/AG o ASD, sepa a ely, and
pe o med a new Hypo hesis-D i en (HD)–GWAS. The app oach was applied o a To on o RD sample and a me a-analysis o he
GenLang Conso ium. Fo he To on o sample (n=624), no SNPs eached significance; howe e , by gene-se analysis, he join
con ibu ion o ASD- ela ed genes passed he h eshold (p~1.45 × 10
–2
, h eshold =2.5 × 10
–2
). Fo he GenLang Coho
(n=26,558), SNPs in DOCK7 and CDH4 showed significan associa ion o he NM/AG hypo hesis (sFDR q =1.02 × 10
–2
). To make
he GenLang da ase mo e simila o To on o, we epea ed he analysis es ic ing o samples selec ed o eading/language defici s
(n=4152). In his GenLang selec ed subse , we ound significan associa ion o a locus in e genic be ween BTG3-C21o 91 o bo h
hypo heses (sFDR q < 9.00 × 10
–4
). This s udy con ibu es candida e loci o he gene ics o wo d eading. Da a also sugges ha ,
al hough di e en a ian s may be in ol ed, alleles implica ed in ASD isk may be ound in he same genes as hose implica ed in
wo d eading. This finding is limi ed o he To on o sample sugges ing ha asce ainmen influences gene ic associa ions.
T ansla ional Psychia y (2022) 12:495 ; h ps://doi.o g/10.1038/s41398-022-02250-z
INTRODUCTION
Reading Disabili y (RD), also known as de elopmen al dyslexia, is a
neu ode elopmen al diso de a ec ing child en globally. In No h
Ame ica alone, i a ec s 5–7% o indi iduals [1–6]. RD is
cha ac e ized by di ficul ies wi h wo d eading and spelling,
despi e ypical in elligence and mo i a ion o lea n [7]. A ec ed
child en o en ha e como bid neu ode elopmen al diso de s,
including language o speech impai men s, o a en ion-defici /
hype ac i i y diso de (ADHD) [8]. These ac o s inc ease social
di ficul ies, dec ease sel -es eem, and hinde academic/occupa-
ional success [9–12]. RD, he e o e, ep esen s a majo public
heal h conce n.
The gene ics and unde lying mechanisms o RD a e no ully
known. Twin and amily s udies ini ially demons a ed gene ic
con ibu ions o RD by examining he i abili y wi hin amilies
[3,13]. Resea che s wen on o iden i y specific ch omosomal
egions and genes implica ed in RD ia linkage analysis ollowed
by fine-mapping associa ion s udies. These linked egions and
genes we e suppo ed, o a ying deg ees, by independen
s udies [14] and me a-analyses [15–20]; howe e , sample sizes
we e small by cu en s anda ds yielding low powe and ele a ed
isk o alse-posi i e findings. Mo eo e , some esul s could no be
eplica ed [16,21,22]. The e o e, esea che s called in o ques ion
he obus ness o he genes as candida es o in ol emen in RD.
Despi e hese ca ea s, a numbe o candida e genes iden ified
om linkage/fine-mapping s udies (KIAA0319, KIAA0319L, DCDC2,
DNAAF4 (p e iously called DYX1C1 and EKN1),and ROBO1) we e
linked o neu onal mig a ion, sugges ing a po en ial molecula
mechanism (bu o a c i ical e iew see [23]). These associa ions
we e pe inen as p e ious pos mo em b ain s udies (n< 10)
ound he e o opias and co ical dysplasias, signa u es o al e ed
mig a ion, in RD-a ec ed indi iduals [24,25]. I was heo ized ha
dis up ed neu onal mig a ion (DNM) may be in ol ed in RD
e iology [26,27].
Recei ed: 10 Oc obe 2022 Re ised: 24 Oc obe 2022 Accep ed: 3 No embe 2022
1
Di ision o Expe imen al and T ansla ional Neu oscience, K embil Resea ch Ins i u e, Uni e si y Heal h Ne wo k, To on o, On a io, Canada.
2
P og am in Neu oscience and Men al
Heal h, Hospi al o Sick Child en, To on o, On a io, Canada.
3
Depa men o Physiology, Uni e si y o To on o, To on o, On a io, Canada.
4
Language and Gene ics Depa men ,
Max Planck Ins i u e o Psycholinguis ics, Nijmegen, The Ne he lands.
5
Depa men o Psychology, Hospi al o Sick Child en, To on o, On a io, Canada.
6
Depa men o
Pedia ics, Uni e si y o To on o, To on o, On a io, Canada.
7
Donde s Ins i u e o B ain, Cogni ion and Beha iou , Radboud Uni e si y, Nijmegen, The Ne he lands.
8
Gene ics and
Genome Biology, Hospi al o Sick Child en, To on o, On a io, Canada.
9
Depa men s o S a is ical Sciences and Compu e Science, Facul y o A s and Science and Di ision o
Bios a is ics, Dalla Lana School o Public Heal h, Uni e si y o To on o, To on o, On a io, Canada. *A lis o au ho s and hei a filia ions appea s a he end o he pape .
✉email: [email p o ec ed]on o.ca
www.na u e.com/ p
T ansla ional Psychia y
1234567890();,:
The fi s e idence o implica e allelic a ia ion o hese RD
candida e genes in DNM came om s udies finding ha p o ein
mo i s/domains encoded by he genes we e p edic ed o unc ion
in mig a ion [28–32]. Fu he e idence eme ged om in u e o
knockdown expe imen s o he genes (KIAA0319, KIAA0319L,
DCDC2,andDNAAF4/DYX1C1) in he de eloping b ains o mice o
a s. When gene exp ession was educed, neu al cells did no
mig a e as expec ed om he lowe en icula zone o he highe
co ical pla e [33–38]. Ins ead, mos cells emained in he
en icula o in e media e zones, indica ing dis up ed mig a ion,
albei wi h di e en pa e ns o dis up ion o di e en genes
[33–38]. Expe imen s in which he candida e genes we e o e -
exp essed also esul ed in neu al pheno ypes, including abe an
neu i e ou g ow h (Dcdc2)[39], delayed adial mig a ion
(Kiaa0319)[40], and al e ed axon g ow h and egene a ion
(Kiaa0319)[41].
The e was, howe e , skep icism ega ding he p oposed oles o
hese genes in mig a ion, when independen knockou expe i-
men s did no eplica e he esul s o he knockdown s udies
[23,40,42–44]. Disc epancies be ween knockou and knockdown
findings may be due o de elopmen al compensa ion by al e ed
gene exp ession [45,46]. Fo example, da a om Dcdc2 knockou
mice suppo s pa ial edundancy wi h Dcx, a membe o he same
gene amily, which unc ionally compensa es o he loss o Dcdc2
[43]. O e all, i emains unclea a his ime whe he he candida e
genes in ques ion a e indeed implica ed in RD and i his in ol es
e ec s on neu onal mig a ion [23].
To u he iden i y genes implica ed in RD, and as he
a ailable echniques ad anced, he field mo ed away om
linkage analysis in amilies o genome-wide associa ion s udies
(GWAS) -- a mo e powe ul app oach o complex ai s in which
e ec sizes o indi idual isk a ian s a e small. In he las ew
yea s, GWAS o RD, eading pe o mance, and/o eading-
ela ed asks ha e begun o yield esul s wi h genome-wide
s a is ical significance (SNP-based analysis (p~10
–8
)[47–50];
gene-based analysis (p~10
–6
)[51–53]). Ac oss ecen significan
and p e ious non-significan GWAS findings, a numbe o he
op genes a e hough o be in ol ed in neu onal mig a ion/
axon pa hfinding, po en ially suppo ing he DNM hypo hesis.
Fo example, in a GWAS by P ice e al., 2020, using wo samples,
he To on o (n=624) and Philadelphia Neu ode elopmen al
Coho (n=4430), he mos significan SNP (p<5×10
–7
)in he
To on osamplewasloca edinanin ono ARHGAP23,agene
in ol ed in ac in cy oskele on polyme iza ion/ eo ganiza ion,
neu onal de elopmen , and o he g ow h cone/axon ela ed
p ocesses [54]. Ac oss bo h samples in ha s udy, when op-
anked SNPs, a a less s ingen p- alue h eshold (p~10
–5
),
we e mapped in o o nea close p oximi y genes, addi ional
genes we e ound o ha e been p e iously ela ed o neu onal
mig a ion/axon guidance (NM-AG) (as well as g ow h cone
o ma ion which is encompassed wi hin his e m). Fo example,
ASTN2,CNTN,TUBB3,NRCAM,DSCAM,UNC5D,andGAP43 [53].
La ge GWAS s udies also p o ided weak suppo o he DNM
hypo hesis. A me a-analysis o 22 samples (n~34,000) by he
GenLang Conso ium, iden ified genome-wide significan a -
ian s in DOCK7 associa ed wi h wo d eading [47]. DOCK7 is
c i ical o co ical neu ogenesis, axon o ma ion, and neu al
pola iza ion [55]. In he la ges GWAS s udy o da e, analyzing
he 23andMe coho , he au ho s iden ified 42 significan loci
associa ed wi h sel - epo ed dyslexia (n
cases
~51,000) o which
genes had been p e iously ela ed o NM/AG [48](Na u e
Gene ics,inp essh ps://doi.o g/10.1101/2021.08.20.21262334).
Howe e , i should be no ed, a sys ema ic a ge ed gene-se
analysis in ha sample ound significan o e ep esen a ion o
genes ela ed o axon guidance bu no o hose in ol ed in
neu onal mig a ion [48].
The P ice e al. s udy also iden ified, a he less s ingen
p- alue h eshold (p~10
–5
), a ian s in o nea genes implica ed
in neu ode elopmen al diso de s, pa icula ly au ism spec um
diso de (ASD) [53]. Fo example, ANKS1B,CNTN4,RBFOX1,
CSMD1,andASTN2. The s udy o he sel - epo ed dyslexia in
23andme obse ed op associa ed SNPs in ASD- ela ed genes.
Al hough he e is li le e idence o suppo pheno ypic
como bidi y be ween ASD and RD, bo h a e neu ode elop-
men al diso de s and ASD in ol es defici s in language and
communica ion skills [56,57]. Fu he , he e is some p elimina y
e idence o sha ed gene ic isk ac o s: a e and de no o
a ian s iden ified in ASD cases o genes ha ha e been
independen ly associa ed wi h RD (PRTG,ROBO1, and
KIAA0319L)[58,59], and al e ed neu onal mig a ion has been
sugges ed as a e iological mechanism in each condi ion
[60–64]. While pu a i e links be ween RD and DNM ha e
ecei ed much a en ion in p io li e a u e, ew in es iga ions o
da e ha e explo ed po en ial o e laps in neu obiological
ounda ions o RD and ASD.
Gi en GWAS-based obse a ionso associa edSNPsingenes
p e iously implica ed in ASD and genes in ol ed in NM/AG,
along wi h in es iga ions o DNM in p e ious candida e gene
and pos mo em s udies, we wished o le e age his in o ma-
ion o imp o e powe o iden i y significan a ian s. Mos
exis ing GWAS samples a e modes in size, wi h he excep ion
o [47,48], and ela i ely ew findings each s a is ical
significance a he genome-wide le el. To le e age powe
wi hin a ailable samples, we used Hypo hesis-D i en
(HD)–GWAS, which up-weigh s o p io i izes a ian s based
on p e iously es ablished gene ic o biological hypo heses
[65]. S a is ical co ec ions a e pe o med independen ly on
he up-weigh ed and nonup-weigh ed g oups, educing he
h eshold o significance and inc easing powe . The HD-GWAS
was p ima ily conduc ed on he To on o sample [53]. We also
wan ed o examine he issues in he con ex o a la ge da ase ,
so seconda ily we used he me a-analysis o he GenLang
Conso ium [47]. A e ia y analysis was conduc ed using only
hose GenLang samples ha we e selec ed based on eading
and/o language di ficul ies, o make i mo e compa able o he
To on o samples.
Fo ou HD-GWAS o wo d eading, we o mula ed wo sepa a e
hypo heses based on he esul s om p e ious GWAS (“con en-
ional”,hypo hesis- eeGWAS)[53] and he li e a u e. Specifically,
we hypo hesized ha a ian s in (1) genes implica ed in NM/AG and
(2) genes implica ed in ASD, would con ibu e o wo d eading.
METHODS
S udy popula ions and measu es
To comple e he HD-GWAS analyses, summa y s a is ics om he To on o
con en ional GWAS [53] and he me a-analysis o he GenLang Conso ium
we e used [47]. The gene-se analyses made use o he aw geno ypes o
he To on o sample and he summa y s a is ics o GenLang. Fo bo h
samples, quan i a i e measu es o wo d eading we e used as he
pheno ype.
To on o sample. The To on o sample has p e iously been desc ibed and
is pa o an ongoing gene ic s udy o RD-selec ed amilies ec ui ed a he
Hospi al o Sick Child en [53,56,66]. A he ime o analysis, he sample
consis ed o child en iden ified wi h eading di ficul ies (n=453) and bo h
hei una ec ed and a ec ed siblings (n=171). Child en we e o Eu opean
ances y, as de e mined by PCA analysis. This choice aimed o educe
a ia ion and c ea e a mo e homogeneous popula ion; howe e , i does
no ully encompass he complex na u e o allelic s uc u e [67]. Child en
we e excluded i he e was e idence o o he neu ode elopmen al
diso de s, including ASD, ap axia, dysp axia, cen al audi o y p ocessing
diso de , s u e ing, and psychia ic diso de s, as well as medical condi ions
ha would in e e e wi h eading. In o ma ion on psychia ic and
neu ode elopmen al diso de s was ob ained using a s uc u ed pa en
in e iew [68] and a semi-s uc u ed eache in e iew [69]. Child en wi h
ADHD, mild anxie y diso de s, and speech/language di ficul ies we e
included.
K.M. P ice e al.
2
T ansla ional Psychia y (2022) 12:495
The To on o sample was measu ed o wo d eading using he Wide
Range Achie emen Tes (WRAT) 3 [70]. The mean eading sco e was 88.4
[53]. Ve bal assen and/o w i en consen was ob ained om all child en
and pa en s. P ocedu al app o al was gi en by he Hospi al o Sick
Child en and Uni e si y Heal h Ne wo k Resea ch E hics Boa ds.
The GenLang Conso ium. The GenLang Conso ium is a la ge in e na-
ional e o o s udy gene ic con ibu ions o ai s ela ed o speech,
language, and eading (h ps://www.genlang.o g). I does so h ough
me a-analyses o hese ai s in popula ion-based samples, as well as
amily-based and case-con ol coho s [47]. Fo he pu poses o he cu en
s udy, he To on o sample was analyzed sepa a ely, because he o e lap
be ween RD and neu onal mig a ion/ASD was o iginally obse ed in his
sample and o med he basis o he hypo heses being es ed in his wo k.
The GenLang me a-analysis da ase used in his s udy consis ed o
17 samples (n=26,588) wi h indi iduals o Eu opean ances y, as de e mined
by PCA analysis (Table S1) [47]. Da a quali y con ol and fil e ing we e
pe o med by each indi idual sample be o e he me a-analysis [47]. We e e
o his sample collec i ely as “The GenLang Coho ”.
In he GenLang Coho , wo d eading was measu ed using a a ie y o
s anda dized es s (depending on he indi idual sample) [47]. These
pheno ypic da a we e aligned ac oss samples p io o he me a-analysis, as
desc ibed in [47]. Consen was ob ained om all pa icipan s in he GenLang
Conso ium and each indi idual sample’s ins i u ion-app o ed da a use.
The GenLang selec ed subse . Fi e samples o he GenLang Coho ,
selec ed o eading o language di ficul ies, we e also examined (n=4152,
Table S1) as a subse . Wi h excep ion o he SLIC coho , all samples we e
selec ed o eading di ficul ies and pa icipan s we e be ween he ages o
7 o 18. We e e o his collec i ely as he “GenLang selec ed subse ”.In
he amily-based samples, pheno ypic da a was a ailable bo h om
p obands and hei siblings, ega dless o a ec ion s a us; he e o e, hese
samples included a ange o quan i a i e a ia ion.
Da a p ocessing and GWAS o To on o. Geno yping and quali y con ol o
he To on o sample we e p e iously desc ibed [53]. B iefly, DNA om each
pa icipan was geno yped on he OmniExp ess pla o m and unobse ed
a ian s we e impu ed using he Michigan impu a ion se e [71]. Quali y
con ol was conduc ed o e nume ous s eps. Sex was checked using he
he e ozygosi y o ma ke s on he X ch omosome. Sibling ela ionships
we e confi med gene ically and indi iduals wi h c yp ic ela ionship we e
emo ed. In addi ion, a ian s wi h low impu a ion quali y (R
2
< 0.3),
a ian s ou o Ha dy-Weinbe g equilib ium (p< 0.0001), and a ian s wi h
mino allele equencies less han 5% we e emo ed as well as samples
wi h >2% missing geno ypes and call a es <98%. A e his fil e ing, 5.3
million SNPs we e included in he analysis.
Because he To on o sample included sibling pai s, he GWAS analysis
was conduc ed using a linea mixed model in he R package ‘nlme’ o
include a andom e ec s e m o amily ela ionship [53]. Co a ia es o
popula ion s uc u e (p incipal componen s) we e also included as fixed
e ec s. Only sel - epo ed Eu opean Caucasian indi iduals we e included
in he analysis; e ified by geno ype. P incipal componen s we e gene a ed
in he p og am KING [72] and a T acy-Widom s a is ic (EIGENSOFT
P og am) was used o de e mine significance [53].
Me a-analysis o he GenLang Coho . Geno yping and quali y con ol o
he GenLang Coho samples we e p e iously desc ibed [47]. Indi idual
coho associa ion analyses we e pe o med wi h di e en ools, including
SNPTEST [73], GEMMA [74], and PLINK [75] and included co a ia es o
popula ion s uc u e (p incipal componen s) and amily ela ionship.
A me a-analysis was pe o med on he samples using he p og am
METAL [76]
,
again using only indi iduals o Eu opean ances y as
de e mined by p incipal componen s. E ec size es ima es we e weigh ed
wi h he in e se o he s anda d e o s and genomic con ol on [47]. The
GenLang selec ed subse unde wen he same me a-analysis p ocess.
Summa y s a is ics o he GenLang Coho s we e p o ided o use in his
s udy a e e iew and app o al o he p ojec by he coo dina ing boa d o
he GenLang Conso ium.
The Manha an and quan ile-quan ile plo s we e gene a ed using FUMA
[77]. The egional associa ion plo was examined in LocusFocus (h ps://
locus ocus. esea ch.sickkids.ca/)[78].
Fo bo h he GenLang Coho and GenLang selec ed sample, only SNPs
wi h a MAF ≥5%, and a ian s p esen in ≥50% o he o al sample
we e used.
HD-GWAS. HD-GWAS se es as a powe ul app oach o GWAS by
inco po a ing gene ic o biological hypo heses based on he p e iously
conduc ed esea ch. This echnique was de eloped and hen es ed by
[65,79–81]. Va ian s a e di ided in o wo s a a: a s a um whe e i is
hypo hesized ha a ian s a e associa ed wi h he ai and a s a um
whe e hey a e no . An es ima ed alse disco e y a e (FDR) is hen
calcula ed sepa a ely on each s a um. This p io i iza ion leads o a less
s ingen ype 1 e o cu -o and inc eases he powe o de ec
associa ed SNPs.
Al hough he To on o sample did no o iginally mee SNP-based
significance in he con en ional GWAS, i did p oduce SNP le el p- alues
o 10
–7
and significan e idence by gene-based analysis. Thus, FDR
co ec ion was app op ia e o inc ease powe . The GenLang sample was a
powe ul sample wi h significan findings by con en ional GWAS.
HD-GWAS was un using he s a ified False Disco e y Ra e (sFDR)
amewo k and p og am (h p://www.u s a . o on o.edu/sun/So wa e/SFDR/
index.h ml)[65,79,80]. As inpu , he p og am equi es a SNP iden ifie , he p-
alue, and he weigh ing s a us (1- no up-weigh ed (no p io i ized), 2- up-
weigh ed (p io i ized)). R (h ps://www. -p ojec .o g/) and he command
“me ge ()”we e hen used o inco po a e up-weigh ing in o ma ion wi h
summa y s a is ics. Va ian s ha we e no in he up-weigh ed g oup o med
he con ol s a um. The sFDR commands “-assoc”and “-SFDR”we e used. The
ou pu included he FDR q- alue and a sFDR q- alue.
To es he fi s hypo hesis, we up-weigh ed a ian s in genes implica ed in
NM/AGaswellasg ow hcone o ma ion.Thegenelis wasmadewi hAmiGO
(h p://amigo.geneon ology.o g), which uses he Gene On ology (GO) da abase
o anno a e genes. The ollowing sea ch e ms we e used GO:0001764 neu on
mig a ion, GO:0007411 axon guidance, and GO:0030426 g ow h cone.
We b oadened neu onal mig a ion o include axon guidance and g ow h
cone o ma ion because many axon guidance molecules a e pleio opic, wi h
di e se unc ions in mul iple issues and in he b ain, including neu onal
mig a ion in he de eloping b ain [82,83] and g ow h cones a e a he ips o
he leading p ocesses o mig a ing neu ons and elonga ing axons [82,83].
Genes in all h ee pa hways ha e been implica ed in diso de s o neu onal
mig a ion, including pe i en icula nodula he e o opia [84], a neu onal
mig a ion diso de in which co ical de elopmen is comp omised, leading o
epilepsy and RD [85]. A o al o ~115,000 a ian s in 351 genes we e es ed
(Table S2). Wi hin his gene lis , we included he o iginal RD-linked candida e
genes ha ha e been implica ed in neu onal mig a ion (KIAA0319, DCDC2,
DYX1C1, and ROBO1).
To es he second hypo hesis, we up-weigh ed a ian s in genes implica ed
in ASD using he gene lis om he Simons Founda ion Au ism Resea ch
Ini ia i e (SFARI) da abase (h ps://gene.s a i.o g/da abase/human-gene/). Mo e
han hal o hese genes ha e been implica ed in ASD h ough a e de no o
mu a ions, o copy numbe a ian s (CNVs, synd omic o unc ional), bu we
also included hose iden ified ia genome-wide associa ion s udies. All
ca ego ies we e included, which a he imeo heanalysisconsis edo 990
genes (Table S3) (~370,000 a ian s).
Gene-se analysis. The join con ibu ion o he genes anno a ed o each
hypo hesis was es ed using gene-se analysis in MAGMA [86]. Fo he NM/
AG and ASD hypo heses, he AMIGO and he SFARI gene lis s, espec i ely,
we e used.
Gene-se analysis in ol es h ee s eps, which we e comple ed in MAGMA
(h ps://c g.cnc .nl/so wa e/magma). Fo he fi s s ep genes we e anno-
a ed o SNPs. Inpu o his s ep was aw geno ype da a o he To on o
sample and he e e ence da a o he 1000 genomes p ojec o he
GenLang [87]. Second, indi idual gene analysis was comple ed o
de e mine he associa ion be ween each gene and he pheno ype. Fo
bo h samples, his s ep was pe o med using linea eg ession o compu e a
p- alue o each gene. The inpu da a we e as ollows. Fo he To on o
sample, he p edic o a iables we e gene anno a ions om he p e ious
s ep and p incipal componen s o popula ion s uc u e. The ou come
a iable was he wo d eading pheno ype. Fo he GenLang da ase s, he
p edic o a iables we e he gene anno a ions om he p e ious s ep and
he ou come was he summa y s a is ic p- alues. Las ly, gene anno a ions
we e agg ega ed o hei se and es ed as a uni o see i hey a ec ed he
ai . MAGMA ook in o conside a ion gene size, gene densi y, and allele
coun . The null hypo hesis was ha he genes es ed as a g oup showed no
g ea e associa ion han a andom se o genes.
Th eshold o significance. The h eshold o significance o he HD-GWAS
and gene-se analyses was se a 2.5 × 10
–2
(c i ical h eshold 0.05/2
hypo heses). The To on o sample o med he basis o ou hypo heses and
K.M. P ice e al.
3
T ansla ional Psychia y (2022) 12:495
was co ec ed sepa a ely om he GenLang me a-analyses. The To on o
sample had no pa icipan o e lap wi h he GenLang Coho .
RESULTS
Con en ional GWAS
The con en ional GWAS o he To on o and he GenLang Coho
ha e p e iously been published [47,53]. The HD-GWAS analyses
u ilized he GenLang Coho wi hou he To on o sample because
he po en ial o e lap be ween eading and neu onal mig a ion/
ASD was o iginally obse ed in ha sample [53].
The GWAS o he GenLang selec ed subse , including only hose
GenLang samples ha we e ec ui ed ia p obands wi h RD o
language diso de , is a no el analysis ha has no p e iously been
desc ibed. The cha ac e is ics o coho s in he selec ed subse a e
a ailable wi hin Supplemen al Table 1 o Eising e al (2022). The
Manha an plo and quan ile-quan ile (Q-Q) plo o he selec ed
subse a e shown in Figs. S1–2. The p alues depa om he
expec ed line in he Q-Q plo a a p alue o 10
−8
. The λs a is ic
was a alue o 1.02.
Fo he con en ional GWAS o he GenLang selec ed subse
(no hypo hesis es ed), he op associa ed locus was on
ch omosome 21q21.1 in he in e genic egion be ween genes
BTG3 and C21o 91. The mos significan SNP was s4818369
(Table 1,p=2.37 × 10
–10
, h eshold p≤5×10
–8
; esul sa
p<10
–6
shown in Table S4). The egional associa ion plo is
depic ed in Fig. S3. Rs4818369 was no ound o co ela e wi h
al e ed splicing o eQTLs. SNPs (p~10
–7
) in linkage disequili-
b ium (LD) (
2
> 0.3) wi h s4818369 a e eQTLs o he genes
BTG3 and C21o 91 (GTEx 8, Table S5). Fo he con en ional
GWAS o he GenLang Coho , his SNP did no show genome-
wide significan associa ion (p=3.00 × 10
–3
).
HD-GWAS o he To on o sample
Fo he HD-GWAS o he To on o sample, no SNPs passed he
h eshold o significance when up-weigh ed based on he wo
hypo heses ( h eshold sFDR q ≤2.5 × 10
–2
; op 10 esul s in Tables
S6–S7). Howe e , when we es ed he join con ibu ion o all
genes in each o he indi idual hypo heses, we ound he ASD-
ela ed gene-se was s a is ically significan (Table 2,
p=1.45 × 10
–2
, h eshold p≤2.5 × 10
–2
).
HD-GWAS o he GenLang Coho
Fo he HD-GWAS o he GenLang Coho , wo loci on ch omosome
1p31.3 and 20q13.33 in DOCK7 and CDH4, espec i ely, passed he
h eshold o significance o he NM/AG hypo hesis. The mos
significan SNP was s1168041 o ch omosome 1 and s6089259
o ch omosome 20 (Table 3, s1168041 p=6.61 × 10
–7
, s6089259
p=7.03 × 10
–6
, bo h sFDR q=1.02 × 10
–2
, h eshold sFDR
q≤2.5 × 10
–2
; esul s wi h q< 0.05 in Tables S8, S10. These SNPs
we e he op anked SNPs by sFDR and in he p io i ized g oup.
Rs1168041 is an eQTL and splice quan i a i e ai locus (sQTL) o
DOCK7, as a e SNPs in LD (
2
> .03) wi h his ma ke (GTEx 8, Table
S9. This SNP is in LD (
2
=.33) wi h he op SNP ( s11208009) in he
o iginal GenLang me a-analysis (22 samples, including he To on o
sample) loca ed ~45 kb om DOCK7 [47]. Rs11208009 is also an
eQTL and sQTL o DOCK7 (Eising e al. (2022) Supplemen a y) [47].
Rs6089259, in onic o CDH4, is no co ela ed wi h al e ed splicing
o eQTLs acco ding o a ailable da a.
Fo he gene-se analysis o he GenLang, no gene-se s passed
he h eshold o significance ( h eshold p ≤2.5 × 10
–2
, Table S11).
HD-GWAS o he GenLang selec ed subse
Fo he HD-GWAS o he GenLang selec ed subse , he same locus
and SNP (21q21.1, s4818369) as he con en ional GWAS passed
he h eshold o significance o bo h hypo heses (Table 4,
p=2.37 × 10
–10
, sFDR q< 9.00 × 10
–4
, 8.00 × 10
−4
, h eshold sFDR
q≤2.5 × 10
–2
; esul s wi h q< 0.05 Tables S12–S13). This SNP was
he op- anked SNP by sFDR and no in he p io i ized g oup,
eflec ing he obus ness o he HD-GWAS [79]. Wi hin he HD-
GWAS and con en ional GWAS o he GenLang selec ed subse , 14
and 18 SNPs, espec i ely, we e p e iously iden ified wi h p < 10
–6
in a p io GWAS analysis o wo d eading by Gialluisi e al. [50]
(Tables S14–S15). The GenLang selec ed subse includes ou
coho s which we e included in he ea lie Gialluisi e al. s udy [50],
al hough a he ime o ha s udy he a o emen ioned coho s
we e smalle in sample size han p esen ly. The GenLang selec ed
subse included one ex a coho (SLIC). The GenLang selec ed
subse comp ised 4152 indi iduals while Gialluisi included 3468
indi iduals.
Fo he gene-se analysis o he GenLang selec ed subse , no
gene-se s passed he h eshold o significance ( h eshold
p≤2.5 × 10
–2
, Table S16).
DISCUSSION
Un il ecen ly, GWAS in es iga ions o eading skills ha e
iden ified ew associa ed loci ha passed he h eshold o
genome-wide significance. Howe e , wi h he o ganiza ion o
la ge-scale collabo a ions, such loci a e beginning o be ound
[47–50]. The numbe and size o coho s cha ac e ized o eading-
ela ed ai s has been a limi ing ac o . The e o e, me hods ha
imp o e powe o capi alize on exis ing samples a e necessa y o
mo e he field o wa d in he sho e m. O e lap wi h op loci and
genes known o be ela ed o NM/AG and ASD suscep ibili y we e
obse ed in p e ious GWAS findings [47,48,53]. To es hese
obse a ions, we used HD-GWAS, p io i izing a ian s in genes
implica ed in NM/AG o ASD suscep ibili y. We also es ed he join
con ibu ion o he genes and he e o e he p io i iza ion
hypo heses hemsel es.
Fo he hypo hesis es ing he ela ionship o ASD, we did no
iden i y significan SNPs by HD-GWAS. Howe e , gene-se analysis
de e mined ha he hypo hesis i sel es ed as he join
con ibu ion o ASD- ela ed genes was significan in he To on o
sample. The e was no ela ionship in he GenLang me a-analysis.
P e ious GWAS s udies ha examined he ela ionship be ween
ASD and RD [47,48,53] did no find gene ic co ela ions using
polygenic isk sco es o LD Sco e Reg ession (LDSC). This may be
Table 1. Con en ional GWAS GenLang selec ed subse only.
SNP Posi ion A1 F eq Gene E ec SE PN
s4818369 21:19055075 T 0.60 BTG3-C21o 91 −0.15 2.43 × 10
–2
2.37 × 10
–10
4152
SNP Single Nucleo ide Polymo phism, Posi ion ch omosome: base pai (hg19), A1 Allele 1, F eq Allele F equency, SE S anda d E o , PP alue, N Sample Size.
Only genome-wide significan esul s shown (significance h eshold p=5×10
−8
).
Table 2. Gene-se esul s o To on o.
Hypo hesis Ngenes Be a SE P
Neu onal Mig a ion/
Axon Guidance
327 0.066 0.048 0.08584
SFARI ASD 890 0.066 0.030 0.01448
Ngenes numbe o genes, SE S anda d E o , PP alue.
Significance h eshold p≤2.5 × 10
−2
.
K.M. P ice e al.
4
T ansla ional Psychia y (2022) 12:495
because he GWAS o ASD o da e a e ela i ely small o because
he coho s we e composed o di e se neu ode elopmen al
pheno ypes as p e iously sugges ed [48]. Fu he , he PRS/LDSC
analyses depend on summa y s a is ics om GWAS analysis, which
use only common a ian s. The SFARI da ase con ains genes
implica ed in ASD by a e a ian s o CNV analyses, as well as
genes iden ified om associa ion s udies o common a ia ion.
Thus, ASD- eading ai o e lap may no be de ec able ia PRS
me hods because a e a ian s we e no impu ed in he GWAS
analyses. Ano he possibili y is ha he e may indeed be sha ed
genes in ol ed, bu ha he specific isk alleles a e di e en o
ASD and eading and a e no in LD. HD-GWAS p io i izes genes
i espec i e o he con ibu ing gene ic a ian s and allows us o
mo e o mally quan i y wo d eading–ASD associa ions in he
To on o sample, which was p e iously an obse a ion [53].
Fo he To on o sample, we excluded child en wi h known o
suspec ed ASD, o wi h a fi s -deg ee ela i e wi h ASD, o o he
global/in ellec ual disabili ies. O e lap be ween eading- and ASD-
associa ed genes likely s emmed om sha ed gene ic isk o
neu ode elopmen al diso de s, pa icula ly hose con ibu ing o
language- ela ed di ficul ies, as opposed o global delays [56,57].
Fo he NM/AG hypo hesis, HD-GWAS using he GenLang
Conso ium da a iden ified wo associa ed loci wi h he op SNPs
loca ed in DOCK7 and CDH4.DOCK7, Dedica o o Cy okinesis 7, is
in ol ed in axon o ma ion and neu onal pola iza ion [55]. The op
ma ke , s1168041, is an eQTL and sQTL o DOCK7. SNPs dis al o
DOCK7 we e p e iously iden ified as significan ly associa ed wi h
wo d eading in he GenLang Conso ium me a-analysis wi h he
op SNPs also eQTLs and sQTLs o DOCK7 [47]. CDH4, Cadhe in 4,
encodes a cell-cell adhesion glycop o ein hough o play a ole in
co ical de elopmen and neu onal ou g ow h [88]. CDH4 has no
been implica ed in RD ai s in p e ious s udies.
Ou HD-GWAS analyses using he selec ed GenLang Conso ium
da a iden ified a significan locus associa ed wi h wo d eading o
bo h hypo heses, indica ing ha he esul is obus and ound
e en hough his locus is no wi hin he upweigh ed SNP se s. The
op associa ed ma ke s ( s4818369) a e loca ed be ween he genes
BTG3 and C21o 91, and LD SNPs a e eQTLs o bo h genes which
a e c edible candida es o in ol emen in RD. BTG3, BTG An i-
P oli e a ion Fac o 3, is implica ed in neu ogenesis [89,90], and
C21o 91, also known as EURL (Ea ly Undi e en ia ed Re ina and
Lens), is implica ed in oligodend oglia di e en ia ion, influencing
he cell’s capaci y o ma u e and o myelina e axons [91].
The esul s o ou HD-GWAS and gene-se analyses, al hough
s a is ically significan in he sepa a e samples, we e no eplica ed
ac oss he To on o and GenLang da ase s. Thus a , ew associa ed
loci ha e been ound o o e lap be ween samples o sel - epo ed
dyslexia, quan i a i e measu es o eading in popula ion-based,
and RD-selec ed coho s [50,53]. None heless, hese same s udies
yield e idence o conside able gene ic o e lap be ween quan i-
a i e measu es o eading and sel - epo dyslexia, as shown by
gene ic co ela ion analyses using he GWAS da a (
g
=−0.71).
The lack o o e lap o indi idual loci may simply be a unc ion o
powe , which could change wi h la ge sample sizes, bu a ole o
di e ences in asce ainmen canno be uled ou . Clinically
asce ained GWAS samples may be en iched o pa icipan s wi h
como bid diso de s as indi iduals wi h mul iple condi ions a e
mo e likely o come o clinical a en ion (Be kson’s Bias) [92],
inc easing he iden ifica ion o genes ela ed o hose diso de s.
Al e na i ely, clinical s udies may sc een o , and exclude
pa icipan s wi h, como bid o medical condi ions o en i on-
men al ac o s ha would in e e e wi h eading acquisi ion. These
exclusions could al e he composi ion o he sample compa ed o
popula ion-based samples and possibly influence gene findings.
In summa y, h ough an HD-GWAS amewo k, we iden ified
significan associa ions wi h eading skills. We also ound ha
genes ela ed o ASD isk con ibu e o RD in he To on o sample.
Ou findings suppo wo co e ea u es o he HD-GWAS ame-
wo k. Fi s , his amewo k is obus o s a i ying misspecifica ion
o up-weigh ed a ian s (i.e., less han ideal hypo heses [65]). We
demons a ed his ea u e when using HD-GWAS we iden ified he
same ch omosomal 21 SNPs om con en ional GWAS, e en
Table 3. HD-GWAS esul s o he GenLang Coho q < 0.05.
Hypo hesis SNP Posi ion Gene P GWAS qSFDR
Neu onal Mig a ion/Axon Guidance s1168041 1:62960250 DOCK7 6.61 × 10
–7
1.02 × 10
–2
s6089259 20:60246390 CDH4 7.03 × 10
–6
1.02 × 10
–2
s17158413 15:83235408 CPEB1 4.42 × 10
–5
2.92 × 10
–2
To al SNPs: 5,552,103.
Upweigh ed SNPs: Neu onal mig a ion 115,448.
SNP Single Nucleo ide Polymo phism, Posi ion ch omosome: base pai (hg19), P GWAS P- alue in GWAS, qSFDR q- alue om SFDR p og am.
Addi ional in o ma ion including LD SNPs o SNPs in same gene egion, ank and up-weigh ed s a us in he supplemen a y ma e ial.
Th eshold o significance q ≤2.5 × 10
−2
.
Table 4. HD-GWAS esul s o GenLang selec ed subse only q < 0.05.
Hypo hesis SNP Posi ion Gene P GWAS qSFDR
Neu onal Mig a ion/Axon Guidance s4818369 21:19055075 BTG3-C21o 91** 2.37 × 10
–10
9.00 × 10
–4
s6090818 20.:46883131 LINC00494** 1.82 × 10
–7
3.67 × 10
–2
s6865160 5:31766737 PDZD2 2.82 × 10
–7
4.10 × 10
–2
SFARI ASD s4818369 21:19055075 BTG3-C21o 91** 2.37 × 10
–10
8.00 × 10
–4
s6090818 20.:46883131 LINC00494** 1.82 × 10
–7
3.50 × 10
–2
s6865160 5:31766737 PDZD2 2.82 × 10
–7
3.92 × 10
–2
To al SNPs: ~5,610,600.
Upweigh ed SNPs: Neu onal mig a ion, 116,829; SFARI ASD 371,158.
SNP Single Nucleo ide Polymo phism, Posi ion ch omosome: base pai (hg19), P GWAS P- alue in GWAS, qSFDR q- alue om SFDR p og am.
Addi ional in o ma ion including LD SNPs o SNPs in same gene egion, ank and up-weigh ed s a us in he supplemen a y ma e ial.
Significance h eshold q ≤2.5 × 10
−2
.
**In e genic and associa ed wi h wo d eading in Gialluisi e al., (6.79 × 10
−6
/3.14 × 10
−7
).
K.M. P ice e al.
5
T ansla ional Psychia y (2022) 12:495
hough hey we e no in he up-weigh ed g oup o he GenLang
selec ed subse . Second, his amewo k inc eases powe o
iden i y genes wi hin hypo hesized pa hways/mechanisms com-
pa ed o uns a ified app oaches. We illus a ed his ea u e when
we ound ha he ASD- ela ed gene-se con ibu ed o eading
and iden ified loci upweigh ed in he NM/AG hypo hesis. Fu u e
s udies in ol ing la ge GWAS samples asce ained h ough
eading and language diso de s may help o elucida e sha ed
gene ic mechanisms be ween RD and ASD.
DATA AVAILABILITY
Summa y s a is ics o he To on o sample and he GenLang sample used in his
s udy a e a ailable upon applica ion o he GenLang Conso ium (h p://
www.genlang.o g) and e iew o he p oposal. To download summa y s a is ics o
he en i e GenLang (no he sample specific o his s udy), use h p://
www.genlang.o g o he public GWAS ca alogue.
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ACKNOWLEDGEMENTS
We hank he psychome is s and olun ee s ha assis ed wi h his p ojec o e he
yea s and he pa icipan s in his s udy. We would like o hank also D . Lei Sun o
he s a is ical guidance using SFDR. Suppo o he To on o p ojec was p o ided by
g an s om he Canadian Ins i u es o Heal h Resea ch (MOP-133440 and PJT-
180419). K.P. was suppo ed by he Hospi al o Sick Child en Resea ch T aining
P og am. E.E. and S.E.F. a e suppo ed by he Max Planck Socie y. GenLang
Conso ium Acknowledgemen s. As s a ed by Eising e al. (2022): B.M., B.M.-M.,
B.S.P., C.F., E.E., E.V., G.A., M. .D., and S.E.F. a e suppo ed by he Max Planck Socie y.
A.G. and T.F.M.A. we e suppo ed by he Munich Clus e o Sys ems Neu ology
(SyNe gy), and A.G. was suppo ed by Fondazione Umbe o Ve onesi. A.T.M. is
suppo ed by Na ional Heal h and Medical Resea ch Council o Aus alia (NHMRC)
G an s 1105008 and 1195955 and Cen e o Resea ch Excellence G an 1116976.
A.J.O.W. is suppo ed by NHMRC G an 1173896. B.S.P. is suppo ed by Simons
K.M. P ice e al.
7
T ansla ional Psychia y (2022) 12:495
Founda ion Au ism Resea ch Ini ia i e G an 514787. C.Y.S. wo ks in he Medical
Resea ch Council In eg a i e Epidemiology Uni a he Uni e si y o B is ol
(MC_UU_00011/3). D.I.B. acknowledges Royal Ne he lands Academy o Science
P o esso Awa d PAH/6635. E.E. is suppo ed by NIH G an R01DC016977. E.G.W. and
J.R.G. a e suppo ed by Na ional Ins i u e o Child Heal h and Human De elopmen
(NICHD) G an P50 HD 27802. F.R. is suppo ed by Agence Na ionale de la Reche che
G an s ANR-06-NEURO-019-01, ANR-17-EURE-0017 IEC, ANR-10-IDEX-0001-02 PSL,
and ANR-11-BSV4-014-01 and Eu opean Commission G an LSHM-CT-2005-018696.
H.T. is suppo ed by he Ne he lands O ganiza ion o Scien ific Resea ch (NWO) and
Ne he lands O ganisa ion o Heal h Resea ch and De elopmen (ZonMW) G an VICI
016.VICI.170.200. J.C.D. was suppo ed by NICHD G an P50 HD 27802. J.J.M., J.B.To.,
and T.K. we e suppo ed by NIH G an R01 DC014489. K.M.P. was suppo ed by he
Hospi al o Sick Child en Resea ch T aining P og am (Res acomp). K.R. is suppo ed
by a Si Hen y Wellcome Pos doc o al Fellowship (213514/Z/18/Z). M.J.S. is suppo ed
by Wellcome T us G an WT082032MA. S.P. and F.A. a e suppo ed by Royal Socie y
G an s UF150663 and RGF EA 180141. T.B. is suppo ed by Ins i u Pas eu , he
Be encou -Schuelle Founda ion, and Uni e si é de Pa is. The Adolescen B ain
Cogni i e De elopmen S udy is suppo ed by he NIH and addi ional ede al
pa ne s (NIH G an s U01DA041048, U01DA050989, U01DA051016, U01DA041022,
U01DA051018, U01DA051037, U01DA050987, U01DA041174, U01DA041106,
U01DA041117, U01DA041028, U01DA041134, U01DA050988, U01DA051039,
U01DA041156, U01DA041025, U01DA041120, U01DA051038, U01DA041148,
U01DA041093, U01DA041089, U24DA041123, and U24DA041147). The As on Coho
was suppo ed by unding om Eu opean Union (EU) Ho izon 2020 P og amme
641652 and Wa e loo Founda ion G an 797/17290. The S . And ews Bioin o ma ics
Uni is unded by Wellcome T us G an s 105621/Z/14/Z and 204821/Z/16/Z. ALSPAC
is suppo ed by UK Medical Resea ch Council and Wellcome G an 217065/Z/19/Z
and he Uni e si y o B is ol. A comp ehensi e lis o g an unding is a ailable on he
ALSPAC websi e (h p://www.b is ol.ac.uk/alspac/ex e nal/documen s/g an -
acknowledgemen s.pd ). The Basque Cen e on Cogni ion, B ain and Language
(BCBL) coho was suppo ed by he Basque Go e nmen h ough he Basic
Excellence Resea ch Cen e p og am and he Agencia Es a al de In es igación
h ough BCBL Se e o Ochoa excellence acc edi a ion. The B isbane Adolescen Twin
Sample was suppo ed by Aus alian Resea ch Council G an s A7960034, A79906588,
A79801419, DP0212016, and DP0343921, wi h geno yping unded by he NHMRC
G an 389891. The Colo ado Lea ning Disabili ies Resea ch Cen e coho was
suppo ed by NICHD G an P50 HD 27802. The Ea ly Language in Vic o ia S udy was
suppo ed by NHMRC G an 436958. The Familial Influences on Li e acy Abili ies
coho is suppo ed by he Uni e si y o Ams e dam, he Max Planck Ins i ue
Nijmegen, and NWO G an s Rubicon 446-12-005 and VENI 451-15-017. The Iowa
s udy was unded by DC00496 and DC02746 om he Na ional Ins i u e on Dea ness
and O he Communica ion Diso de s (NIDCD). The GRaD s udy was unded by he
Man on Founda ion, NIH G an s P50-HD027802 and K99-HD094902, and he Lambe
Family. Neu oDys was unded by an EU Six h F amewo k P og am g an o he
Neu oDys Conso ium, Swiss Na ional Science Founda ion G an 32-108130, and
Aus ian Science Fund G an 18351-B02. The Ne he lands Twin Regis e is unded by
NWO G an s 480-04-004, 481-08-011, 056-32-010, 024.001.003, 480-15-001/674,
184.021.007, 184.033.111, and 56-464-14192; ZonMW G an s 911-09-032 and 912-
10-020; he Ams e dam Public Heal h and Ams e dam Rep oduc ion and De elop-
men Resea ch Ins i u es; Eu opean Science Council G an ERC Ad anced 230374; EU
Se en h F amewo k P og am (FP7) G an FP7/2007-2013: 602768; Na ional Ins i u e
o Men al Heal h (NIMH) G an s U24 MH068457-06, R01 MH58799-03, and 1RC2
MH089995; and he A e a Ins i u e o Human Gene ics. The Pedia ic Imaging,
Neu ocogni ion, and Gene ics coho is unded by NIH G an RC2DA029475, he
Na ional Ins i u e on D ug Abuse, and he Eunice Kennedy Sh i e NICHD. The
Philadelphia Neu ode elopmen al Coho is unded by NIH G an s RC2MH089983
and RC2MH089924, an ins i u ional de elopmen awa d o he Cen e o Applied
Genomics om The Child en’s Hospi al o Philadelphia, and a dona ion om Adele
and Daniel Kube and hanks he NIH da a eposi o y. The Raine s udy was
suppo ed by long- e m unding om NHMRC G an s 572613, 403981, 1059711,
634445, 634509, and 1021105 and Canadian Ins i u es o Heal h Resea ch (CIHR)
G an MOP-82893. Funding was also p o ided by he Uni e si y o Wes e n Aus alia,
Cu in Uni e si y, he Women and In an s Resea ch Founda ion, he Tele hon Kids
Ins i u e, Edi h Cowan Uni e si y, Mu doch Uni e si y, he Uni e si y o No e Dame
Aus alia, and he Raine Medical Resea ch Founda ion. The Raine s udy analyses we e
suppo ed by he Pawsey Supe compu ing Cen e wi h unding om he Aus alian
Go e nmen and he Go e nmen o Wes e n Aus alia. The Saguenay You h S udy is
suppo ed by he CIHR, he Hea and S oke Founda ion o Quebec, and he
Canadian Founda ion o Inno a ion. The SLI Conso ium was unded by Wellcome
T us G an 076566 and UK Medical Resea ch Council G an G1000569. The Twins
Ea ly De elopmen S udy is suppo ed by UK Medical Resea ch Council G an s MR/
V012878/1 and MR/M021475/1, NIH G an AG046938, and he EU FP7 g an FP7/
2007-2013/: 602768. To on o was suppo ed by CIHR G an MOP-133440. UK Dyslexia
was suppo ed by Wellcome T us G an s 076566/Z/05/Z and 075491/Z/04, Wa e loo
Founda ion G an 797–1720, EU G an 018696, and Royal Socie y G an UF100463.
The Yo k coho was unded by Wellcome T us G an 082036/B/07/Z.
AUTHOR CONTRIBUTIONS
KMP, LJS, and CLB designed esea ch; KMP, KGW, YF, KB, MW, ENK, SLG, and EE
pe o med esea ch and analyzed da a; MWL, ENK, SLG MW, KB and CLB collec ed he
To on o coho ; The Quan i a i e T ai Wo king G oup o he GenLang Conso ium
collec ed and analysed he da a on he coho s (led by EE and SEF); KMP and CLB
w o e he pape wi h inpu om all au ho s.
COMPETING INTERESTS
The au ho s decla e no compe ing in e es s.
ADDITIONAL INFORMATION
Supplemen a y in o ma ion The online e sion con ains supplemen a y ma e ial
a ailable a h ps://doi.o g/10.1038/s41398-022-02250-z.
Co espondence and eques s o ma e ials should be add essed o Ca hy L. Ba .
Rep in s and pe mission in o ma ion is a ailable a h p://www.na u e.com/
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QUANTITATIVE TRAIT WORKING GROUP OF THE GENLANG CONSORTIUM
Filippo Abbondanza10, And ea G. Alleg ini11, Till F. M. Andlaue 12,13, Ca hy L. Ba 1,2,3 ✉, Timo hy C. Ba es14, Manon Be na d15,
Ki s en Blokland2, Milene Bon e16, Do e I. Boomsma17,18,19, Thomas Bou ge on20,21, Daniel B andeis22,23,24,25, Manuel Ca ei as26,27,28,
Fabiola Ce oni29,30, Valé ia Csépe31,32, Philip S. Dale33, John C. DeF ies34,35, Pe e F. de Jong36, Jean F ancois Démone 37, E eline L. de
Zeeuw18, Else Eising 4, Yu Feng1, Simon E. Fishe 4,7, Ma ie-Ch is ine J. F anken38, Clyde F ancks4,7,39, Ma go Ge i se4,
Alessand o Gialluisi12,40,41, Sco D. Go don42, Je ey R. G uen43, Sha on L. Guge 5, Ma ianna E. Hayiou-Thomas44, Juan He nández-
Cab e a45, Jouke-Jan Ho enga18, Cha les Hulme46, Philip R. Jansen47,48,49, Juha Ke e50,51, Elizabe h N. Ke 5,6, Tanne Kooma 52,
Ka in Lande l53,54, Gab iel T. Leona d55, Zhijie Liao56, Mau een W. Lo e 2,6, Michelle Luciano14, Heikki Lyy inen57, Nicholas G. Ma in42,
Angela Ma inelli10, U s Mau e 58, Jacob J. Michaelson52, Nazanin Mi za-Sch eibe 59, K is ina Moll60, An hony P. Monaco61,
Angela T. Mo gan62,63,64, Be am Mülle -Myhsok12,65, Dianne F. Newbu y30, Ma kus M. Nö hen66, Richa d K. Olson34,35,
K.M. P ice e al.
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T ansla ional Psychia y (2022) 12:495
Sil ia Pa acchini10, Tomas Paus67,68,69, Zdenka Pauso a15,70, C aig E. Pennell71,72,73, B uce F. Penning on74, Robe J. Plomin11,
Kai lyn M. P ice1,2,3, F anck Ramus75, Sheena Reilly62,76, Louis Riche 77, Kaili Rim eld11,78, Ge d Schul e-Kö ne60, Chin Yang Shapland79,80,
Nuala H. Simpson81, Shelley D. Smi h82, Ma ga e J. Snowling81,83, Bea e S Pou cain4,7,79, John F. S ein84, Lisa J. S ug8,9, Joel B. Talco 85,
Henning Tiemeie 47,86, J. B uce Tomblin87, Dongnhu T. T uong43, Elsje an Be gen17,18,88, Ma c P. an de Sch oe 38,89, Ma jolein Van
Donkelaa 4, Ellen Ve hoe 4, Ca ol A. Wang71,72, Ka e E. Wa kins81, And ew J. O. Whi ehouse90, Ka en G. Wigg1, E ik G. Willcu 34,35,
Ma ga e Wilkinson2, Ma ga e J. W igh 91 and Gu Zhu42
10
School o Medicine, Uni e si y o S And ews, KY16 9TF S . And ews, Sco land.
11
Social, Gene ic and De elopmen al Psychia y Cen e, Ins i u e o Psychia y, Psychology and
Neu oscience, King’s College London, London, UK.
12
T ansla ional Resea ch in Psychia y, Max Planck Ins i u e o Psychia y, Munich, Ge many.
13
Depa men o Neu ology,
Klinikum ech s de Isa , School o Medicine, Technical Uni e si y o Munich, Munich, Ge many.
14
Depa men o Psychology, Uni e si y o Edinbu gh, Edinbu gh EH8 9JZ, UK.
15
Depa men o Physiology and Nu i ional Sciences, Uni e si y o To on o, To on o, ON M5S 1A1, Canada.
16
Depa men o Cogni i e Neu oscience and Maas ich B ain
Imaging Cen e , Facul y o Psychology and Neu oscience, Maas ich Uni e si y, Maas ich , The Ne he lands.
17
Ne he lands Twin Regis e , Ams e dam, The Ne he lands.
18
Depa men o Biological Psychology, V ije Uni e si ei Ams e dam, 1081 BT Ams e dam, The Ne he lands.
19
Ams e dam Rep oduc ion and De elopmen (AR&D) Resea ch
Ins i u e, Ams e dam, UMC, The Ne he lands.
20
Human Gene ics and Cogni i e Func ion Uni , Ins i u Pas eu , Pa is, F ance.
21
Cen e Na ional Reche che Scien ifique (CNRS) UMR
3571, Uni e si é de Pa is, Pa is, F ance.
22
Depa men o Child and Adolescen Psychia y and Psycho he apy, Psychia ic Uni e si y Hospi al Zu ich, Uni e si y o Zu ich, 8032
Zu ich, Swi ze land.
23
Zu ich Cen e o In eg a i e Human Physiology, Uni e si y o Zu ich and ETH Zu ich, 8057 Zu ich, Swi ze land.
24
Neu oscience Cen e Zu ich, Uni e si y o
Zu ich and ETH Zu ich, 8057 Zu ich, Swi ze land.
25
Depa men o Child and Adolescen Psychia y and Psycho he apy, Cen al Ins i u e o Men al Heal h, Medical Facul y
Mannheim, Heidelbe g Uni e si y, 68159 Mannheim, Ge many.
26
Basque Cen e on Cogni ion, B ain and Language (BCBL), Donos ia-San Sebas ian, Gipuzkoa, Spain.
27
Ike basque, Basque Founda ion o Science, Bilbao, Vizcaya, Spain.
28
Lengua Vasca y Comunicación, Uni e si y o he Basque Coun y (UPV/EHU), Bilbao, Vizcaya, Spain.
29
Depa men o Pha macy and Bio echnology, Uni e si y o Bologna, 40126 Bologna, I aly.
30
Facul y o Heal h and Li e Sciences, Ox o d B ookes Uni e si y, Ox o d OX3 0BP, UK.
31
B ain Imaging Cen e, Resea ch Cen e o Na u al Sciences, Budapes 1117, Hunga y.
32
Mul ilingualism Doc o al School, Facul y o Mode n Philology and Social Sciences,
Uni e si y o Pannonia, Veszp ém 8200, Hunga y.
33
Depa men o Speech & Hea ing Sciences, Uni e si y o New Mexico, Albuque que, NM 87131, USA.
34
Ins i u e o Beha io al
Gene ics, Uni e si y o Colo ado, Boulde , CO 80309-0447, USA.
35
Depa men o Psychology and Neu oscience, Uni e si y o Colo ado, Boulde , CO 80309-0447, USA.
36
Depa men o Child De elopmen and Educa ion, Uni e si y o Ams e dam, 1012 WX Ams e dam, The Ne he lands.
37
Leenaa ds Memo y Cen e, Depa men o Clinical
Neu osciences, Lausanne Uni e si y Hospi al (CHUV), Uni e si y o Lausanne, CH-1011 Lausanne, Swi ze land.
38
Depa men o O ola yngology, Head and Neck Su ge y, E asmus
Uni e si y Medical Cen e , 3015 GD Ro e dam, The Ne he lands.
39
Depa men o Human Gene ics, Radboud Uni e si y Medical Cen e , 6525 GA Nijmegen, The Ne he lands.
40
Depa men o Epidemiology and P e en ion, IRCCS Is i u o Neu ologico Medi e aneo Neu omed, Pozzilli, I aly.
41
EPIMED Resea ch Cen e , Depa men o Medicine and
Su ge y, Uni e si y o Insub ia, Va ese, I aly.
42
Gene ic Epidemiology Labo a o y, QIMR Be gho e Medical Resea ch Ins i u e, B isbane, QLD 4006, Aus alia.
43
Depa men s o
Pedia ics and Gene ics, Yale Medical School, New Ha en, CT 06510, USA.
44
Depa men o Psychology, Uni e si y o Yo k, Yo k YO10 5DD, UK.
45
Depa amen o de Psicología,
Clínica Psicobiología y Me odología, 38200La Laguna, San a C uz de Tene i e, Spain.
46
Depa men o Educa ion, Uni e si y o Ox o d, Ox o d, Ox o dshi e OX2 6PY, UK.
47
Depa men o Child and Adolescen Psychia y/Psychology, E asmus Uni e si y Medical Cen e , 3000 CB Ro e dam, The Ne he lands.
48
Depa men o Complex T ai Gene ics,
Cen e o Neu ogenomics and Cogni i e Resea ch, Ams e dam Neu oscience, VU Uni e si y, Ams e dam, The Ne he lands.
49
Depa men o Human Gene ics, VU Medical Cen e ,
Ams e dam Uni e si y Medical Cen e , 1081 BT Ams e dam, The Ne he lands.
50
Depa men o Biosciences and Nu i ion, Ka olinska Ins i u e , 171 77 S ockholm, Sweden.
51
S em
Cells and Me abolism Resea ch P og am, Uni e si y o Helsinki and Folkhälsan Resea ch Cen e , 00014 Helsinki, Finland.
52
Depa men o Psychia y, Uni e si y o Iowa, Iowa Ci y,
IA 52242, USA.
53
Ins i u e o Psychology, Ka l-F anzens-Uni e si ä G az, 8010 G az, Aus ia.
54
BioTechMed-G az, G az, Aus ia.
55
Cogni i e Neu oscience Neu ology and
Neu osu ge y, McGill Uni e si y, Mon eal, QC H3A 1G1, Canada.
56
Depa men o Psychology, Uni e si y o To on o, To on o, ON, Canada.
57
Depa men o Psychology,
Uni e si y o Jy äskylä, 40014 Jy äskylä, Finland.
58
Depa men o Psychology, The Chinese Uni e si y o Hong Kong, Hong Kong, China.
59
Ins i u e o Neu ogenomics, Helmhol z
Zen um München, Munich, Ge many.
60
Depa men o Child and Adolescen Psychia y, Psychosoma ics, and Psycho he apy, Ludwig-Maximilians-Uni e si y Hospi al Munich,
Munich 80336, Ge many.
61
O fice o he P esiden , Tu s Uni e si y, Med o d, MA 02155, USA.
62
Speech and Language, Mu doch Child en’s Resea ch Ins i u e, Melbou ne, VIC
3052, Aus alia.
63
Depa men o Audiology and Speech Pa hology, Uni e si y o Melbou ne, Melbou ne, VIC 3052, Aus alia.
64
Speech Pa hology Depa men , Royal Child en’s
Hospi al, Melbou ne, VIC 3052, Aus alia.
65
Depa men o Heal h Science, Uni e si y o Li e pool, Li e pool L69 7ZX, UK.
66
Ins i u e o Human Gene ics, Uni e si y Hospi al o
Bonn, 53127 Bonn, Ge many.
67
Depa men o Psychia y and Neu oscience and Cen e Hospi alie Uni e si ai e Sain e Jus ine, Uni e si y o Mon eal, Mon eal, QC H3T 1J4,
Canada.
68
Depa men o Psychia y, Uni e si y o To on o, To on o, ON, Canada.
69
Depa men o Psychology, Uni e si y o To on o, To on o, ON, Canada.
70
T ansla ional
Medicine, Hospi al o Sick Child en, To on o, ON, Canada.
71
School o Medicine and Public Heal h, College o Heal h, Medicine and Wellbeing, Uni e si y o Newcas le, Newcas le,
NSW 2308, Aus alia.
72
Mo he s and Babies Resea ch P og am, Hun e Medical Resea ch Ins i u e, Newcas le, NSW 2305, Aus alia.
73
Ma e ni y and Gynaecology, John Hun e
Hospi al, Newcas le, New Sou h Wales, Aus alia.
74
Depa men o Psychology, Uni e si y o Den e , Den e , CO, USA.
75
Labo a oi e de Sciences Cogni i es e Psycholinguis ique,
Ecole No male Supé ieu e, Pa is Sciences & Le es Uni e si y, École des Hau es É udes en Sciences Sociales (EHESS), Cen e Na ional de la Reche che Scien ifique (CNRS), Pa is
75005, F ance.
76
The Heal h G oup, G i fi h Uni e si y, Gold Coas , Queensland, Aus alia.
77
Depa men o Heal h Sciences, Uni e si é du Québec à Chicou imi, Chicou imi, QC,
Canada.
78
Depa men o Psychology, Royal Holloway, Uni e si y o London, Egham TW20 0EY, UK.
79
MRC In eg a i e Epidemiology Uni , Uni e si y o B is ol, B is ol BS8 2BN, UK.
80
Popula ion Heal h Sciences, Uni e si y o B is ol, B is ol BS8 2PS, UK.
81
Depa men o Expe imen al Psychology, Uni e si y o Ox o d, Ox o d OX2 6GG, UK.
82
Depa men o
Neu ological Sciences, College o Medicine, Uni e si y o Neb aska Medical Cen e , Omaha, NE 68198, USA.
83
S John’s College, Uni e si y o Ox o d, Ox o d OX1 3JP, UK.
84
Depa men o Physiology, Ana omy and Gene ics, Ox o d Uni e si y, Ox o d OX1 3PT, UK.
85
Ins i u e o Heal h and Neu ode elopmen , As on Uni e si y, Bi mingham B4 7ET,
UK.
86
T.H. Chan School o Public Heal h, Ha a d, Bos on, MA 02115, USA.
87
Communica ion Sciences and Diso de s, Uni e si y o Iowa, Iowa Ci y, IA, USA.
88
Resea ch Ins i u e
LEARN!, V ije Uni e si ei Ams e dam, Ams e dam, The Ne he lands.
89
Gene a ion R S udy G oup, E asmus MC, Ro e dam, The Ne he lands.
90
Tele hon Kids Ins i u e, The
Uni e si y o Wes e n Aus alia, Pe h, WA 6009, Aus alia.
91
Queensland B ain Ins i u e, Uni e si y o Queensland, B isbane, Queensland, Aus alia.
K.M. P ice e al.
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T ansla ional Psychia y (2022) 12:495
