D1130–D1137 Nucleic Acids Resea ch, 2021, Vol. 49, Da abase issue Published online 29 Sep embe 2020
doi: 10.1093/na /gkaa794
CSVS, a c owdsou cing da abase o he Spanish
popula ion gene ic a iabili y
Ma ´
ıa Pe˜
na-Chile 1,2,3, Gema Rold´
an1, Ja ie Pe ez-Flo ido1,3,4, F ancisco M. O u ˜
no1,3,4,
Rosa io Ca mona1, Vi ginia Aquino1, Daniel Lopez-Lopez1,3, Ca los Louce a1,3, Jose
L. Fe nandez-Rueda1, Asunci´
on Gallego5, F ancisco Ga c´
ıa-Ga cia6,
Anna Gonz´
alez-Nei a7, Guille mo Pi a7,Roc
´
ıo N´
u˜
nez-To es7, Ja ie San oyo-L´
opez8,
Ca men Ayuso9, Pablo Minguez9,10, Almudena A ila-Fe nandez9, Ma a Co on9, Miguel
´
Angel Mo eno-Pelayo11,Ma
´
ıas Mo in11, Al a o Gallego-Ma inez12,13, Jose
A. Lopez-Escamez12,13, Salud Bo ego14,15, Guille mo An i˜
nolo14,15, Jo ge Amigo16,
Jose a Salgado-Ga ido17, Sa a Pasalodos-Sanchez17, Bea iz Mo e18, The Spanish Exome
C owdsou cing Conso ium, ´
Angel Ca acedo16,19,´
Angel Alonso17 and
Joaqu´
ın Dopazo 1,2,3,4,*
1Clinical Bioin o ma ics A ea, Fundaci´
on P og eso y Salud (FPS), Hospi al Vi gen del Roc´
ıo, Se illa 41013, Spain,
2Bioin o ma ics in Ra e Diseases (BiER), Cen e o Biomedical Ne wo k Resea ch on Ra e Diseases (CIBERER),
ISCIII, Se illa 41013, Spain, 3Compu a ional Sys ems Medicine g oup, Ins i u e o Biomedicine o Se ille (IBIS)
Hospi al Vi gen del Roc´
ıo, Se illa 41013, Spain, 4Func ional Genomics Node, FPS/ELIXIR-ES, Hospi al Vi gen del
Roc´
ıo, Se illa 41013, Spain, 5Sis emas Genomicos, Pa e na, Valencia 46980, Spain, 6Unidad de Bioin o m´
a ica y
Bioes ad´
ıs ica, Cen o de In es igaci´
on P ´
ıncipe Felipe (CIPF), Valencia 46012, Spain, 7Human Geno yping
Uni –Cen o Nacional de Geno ipado (CEGEN), Human Cance Gene ics P og amme, Spanish Na ional Cance
Resea ch Cen e (CNIO), Mad id 28029, Spain, 8Edinbu gh Genomics, The Uni e si y o Edinbu gh, Edinbu gh EH9
3FL, UK, 9Depa men o Gene ics, Ins i u o de In es igaci´
on Sani a ia-Fundaci´
on Jim´
enez D´
ıaz Uni e si y Hospi al,
Uni e sidad Au ´
onoma de Mad id (IIS-FJD, UAM), Mad id 28040, Spain, 10Cen e o Biomedical Ne wo k Resea ch
on Ra e Diseases (CIBERER), ISCIII, Mad id 28040, Spain, 11Se icio de Gen´
e ica, Ram´
on y Cajal Ins i u e o
Heal h Resea ch (IRYCIS) and Biomedical Ne wo k Resea ch Cen e on Ra e Diseases (CIBERER), Mad id 28034,
Spain, 12O ology & Neu o ology G oup CTS 495, Depa men o Genomic Medicine, Cen e o Genomics and
Oncological Resea ch (GENYO), P ize Uni e si y o G anada, G anada 18016, Spain, 13Depa men o
O ola yngology, Ins i u o de In es igaci´
on Biosani a ia, IBS. GRANADA, Hospi al Uni e si a io Vi gen de las Nie es,
Uni e sidad de G anada, G anada 18016, Spain, 14Depa men o Ma e no e al Medicine, Gene ics and
Rep oduc ion, Ins i u e o Biomedicine o Se ille (IBIS), Uni e si y Hospi al Vi gen del Roc´
ıo/CSIC/Uni e si y o
Se ille, Se ille 41013, Spain, 15Cen e o Biomedical Ne wo k Resea ch on Ra e Diseases (CIBERER), Se ille
41013, Spain, 16Fundaci´
on P´
ublica Galega de Medicina Xen´
omica, SERGAS, IDIS, San iago de Compos ela 15706,
Spain, 17Na a abiomed-IdiSNA, Complejo Hospi ala io de Na a a, Uni e sidad P´
ublica de Na a a (UPNA), IdiSNA
(Na a a Ins i u e o Heal h Resea ch), Pamplona, Na a a 31008, Spain, 18Undiagnosed Ra e Diseases
P og amme (ENoD). Cen e o Biomedical Resea ch on Ra e Diseases (CIBERER), ISCIII, Mad id 28029, Spain
and 19G upo de Medicina Xen´
omica, Cen o de In es igaci´
on Biom´
edica en Red de En e medades Ra as
(CIBERER), CIMUS, Uni e sidade de San iago de Compos ela, San iago de Compos ela, Espa˜
na
Recei ed Augus 13, 2020; Re ised Sep embe 08, 2020; Edi o ial Decision Sep embe 10, 2020; Accep ed Sep embe 10, 2020
ABSTRACT
The knowledge o he gene ic a iabili y o he lo-
cal popula ion is o u mos impo ance in pe son-
alized medicine and has been e ealed as a c i -
ical ac o o he disco e y o new disease a i-
an s. He e, we p esen he Collabo a i e Spanish
Va iabili y Se e (CSVS), which cu en ly con ains
mo e han 2000 genomes and exomes o un ela ed
*To whom co espondence should be add essed. Tel: +34 677910685; Email: [email p o ec ed]
C
The Au ho (s) 2020. Published by Ox o d Uni e si y P ess on behal o Nucleic Acids Resea ch.
This is an Open Access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion License (h p://c ea i ecommons.o g/licenses/by/4.0/), which
pe mi s un es ic ed euse, dis ibu ion, and ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly ci ed.
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Nucleic Acids Resea ch, 2021, Vol. 49, Da abase issue D1131
Spanish indi iduals. This da abase has been gen-
e a ed in a collabo a i e c owdsou cing e o col-
lec ing sequencing da a p oduced by local genomic
p ojec s and o o he pu poses. Sequences ha e
been g ouped by ICD10 uppe ca ego ies. A web in-
e ace allows que ying he da abase emo ing one
o mo e ICD10 ca ego ies. In his way, agg ega ed
coun s o allele equencies o he pseudo-con ol
Spanish popula ion can be ob ained o diseases be-
longing o he ca ego y emo ed. In e es ingly, in ad-
di ion o pseudo-con ol s udies, some popula ion
s udies can be made, as, o example, p e alence o
pha macogenomic a ian s, e c. In addi ion, his ge-
nomic da a has been used o de ine he i s Spanish
Genome Re e ence Panel (SGRP1.0) o impu a ion.
This is he i s local eposi o y o a iabili y en i ely
p oduced by a c owdsou cing e o and cons i u es
an example o u u e ini ia i es o cha ac e ize local
a iabili y wo ldwide. CSVS is also pa o he GA4GH
Beacon ne wo k.
CSVS can be accessed a : h p://cs s.babelomics.
o g/.
INTRODUCTION
Sequencing echnologies ha e expe ienced an unp ece-
den ed de elopmen du ing he las decade (1) ha esul ed
in di e en in e na ional collabo a i e p ojec s (2–4) which
con ibu ed o an ex ao dina y inc ease in he knowledge
o he mu a ional spec um o diseases. This gene a ion o
knowledge has been especially signi ican in diseases wi h
high mo bidi y and mo ali y, caused by highly pene an
( ypically p o ein-coding) a ian s (5,6). In ac , mo e han
4500 monogenic diseases can nowadays be di ec ly diag-
nosed by pe sonalized genomics (7), a possibili y ha migh
soon be ex ended o he whole spec um o a e diseases
wi h a gene ic backg ound (8). Among he s a egies used
o disco e new disease a ian s, especially in monogenic
diso de s, equency-based il e ing has demons a ed o be
a e yuse ul ool(9). The a ionale is as ollows: a ian s
ha a e ela i ely common in a con ol popula ion (com-
mon a ia ion) a e likely benign (10), while a e a ian s
(especially i hey ha e unc ional consequences) ound in
mul iple a ec ed cases bu absen in he con ol popula ion
a e likely o cause disease (11–13). These il e s sea ch o
genes o a ian s p esen in all (o mos ) a ec ed indi iduals
bu in none (o e y ew) o he una ec ed con ol indi id-
uals. The e o e, i seems clea ha he a ailabili y o heal hy
con ols is a decisi e ac o o he p og ess o disco e y o
new disease de e minan s.
F om an his o ical pe spec i e, he 1000 Genomes P ojec
p oduced he i s comp ehensi e ca alogue o common hu-
man gene ic a ia ion (14). Howe e , i is known ha low
equency (wi h mino allele equencies, MAF, unde 5%)
and a e (MAF unde 0.5%) a ian s, ypically popula ion-
speci ic (15), a e poo ly ep esen ed in such ca alogue (14).
Ac ually, ecen s udies ha e desc ibed a ema kable local
componen (16–18) and a high s a i ica ion le el (19,20)in
many a e a ian s wi h unce ain unc ional consequences.
As a consequence o his, he isk o many diseases di e s in
dis inc human popula ions acco ding o hei gene ic back-
g ounds (21,22). In ac , he knowledge o he gene ic a i-
abili y o he local popula ion has been e ealed as a c i -
ical ac o o he disco e y o new disease a ian s (23).
All hese obse a ions highligh he need o popula ion-
speci ic ca alogues o gene ic a ia ion (24). Howe e , only
a ew ini ia i es o s udy gene ic a ia ion a he popula-
ion le el ha e been ca ied ou o da e, which include a
whole-genome sequence (WGS) s udy o 100 Malays (25),
he Genome o he Ne he lands, wi h low- esolu ion (∼13×)
WGS da a o 250 io- amilies om ac oss he en i e coun-
y (15), he F ench-Canadians s udy o 109 exomes (26),
he Medical Genome P ojec ha p oduced a ca alog o he
heal hy Spanish popula ion wi h almos 270 exomes (23),
he 3000 Finnish genomes (27) and he Icelandic popula ion
s udy o medium esolu ion (∼20×) WGS o 2636 indi idu-
als (28) o he high esolu ion (>30×) WGS o 1070 heal hy
Japanese indi iduals (29) and he ecen gene ic analysis o
he I anian popula ion (30).
In spi e o i s ecognized use ulness, la ge-scale sequenc-
ing p ojec s o coho s o local ‘heal hy’ popula ions equi e
expensi e conso ium-based p ojec s o ob ain a ep esen-
a i e sample o he popula ion a ge ed. Un o una ely,
unding bodies ha a e p one o suppo esea ch on dis-
eases, end o be, howe e , eluc an o und p ojec s ha
in ol e sys ema ic sequencing o heal hy indi iduals. In his
scena io, a c owdsou cing s a egy can p o ide a easible
al e na i e o adi ional wo king schemas by o ganizing
conso ia ha collec da a om di e en g oups ha ul i-
ma ely a e collec i ely bene i ed o he sample size coope -
a i ely ob ained. C owdsou cing is becoming a e y popu-
la s a egy in biomedicine (31) and can be de ined as ‘ he
p ocess o ge ing se ices, in o ma ion, labo o ideas by
ou sou cing h ough an open call, especially h ough he
In e ne ’ (32). Recen ly some examples o c owdsou ced e-
sea ch ha e demons a ed an inc eased accu acy in p edic -
ing b eas cance su i al (33), esponse o d ugs (34)o
o oxic compounds (35) om bo h, clinical and genomic
da a, and show how ‘c owdsou ced da a science challenges
can achie e in mon hs wha would ake yea s h ough con-
en ional esea ch app oaches’ (36).
MATERIALS AND METHODS
Subjec s
The da abase con ains de ailed allelic equencies co -
esponding o The MGP popula ion, sequenced in he
con ex o he Medical Genome P ojec (h p://www.
clinbioin osspa.es/con en /medical-genome-p ojec ),
which includes 267 heal hy, un ela ed samples o Spanish
o igin (EGA, accession: EGAS00001000938), o he heal hy
con ols, pa ien s o di e en diseases, accompanied in
some cases o un ela ed pheno ypically heal hy ca ie s.
The sequences we e con ibu ed by di e en conso iums
and p ojec s, including g oups om he Spanish Ne wo k
o Resea ch in Ra e Diseases, CIBERER, esul s om
he EnoD, (Undiagnosed Ra e Diseases p og amme; h ps:
//www.cibe e .es/en/ ans e sal-p og ammes/scien i ic-
p ojec s/undiagnosed- a e-diseases-p og amme-enod),
he P ojec Genome 1000 Na a a (NAGEN 1000;
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D1132 Nucleic Acids Resea ch, 2021, Vol. 49, Da abase issue
(h ps://www.nagen1000na a a.es/en), The Ra eGenomics
(h ps://www. a e-genomics.com/) om Mad id, and o he
esea ch g oups and ini ia i es ac oss Spain (37,38), which
cu en ly sum up a o al o 2027 genomic and exomic
sequences o un ela ed Spanish indi iduals.
Tes ing sample locali y
Ensu ing he Spanish locali y o he samples uploaded in
he CSVS is key o he p ojec . He e, we speci ically de-
eloped a me hodology o double-check he o igin o each
sample. Sequences belonging o di e en popula ions in
he 1000 genomes p ojec (14)we eused o ainaMa-
chine Lea ning based decision model o disc imina e Span-
ish samples om he es o popula ions. Fi s ly, SNPs co -
esponding o he genomic egions sha ed by all he sam-
ples ha ing a MAF >0.01 we e selec ed. Then, indi idual
ances y in 1000 genomes was es ima ed o 26 subpopu-
la ions using ADMIXTURE (39). The e o e, each indi id-
ual is desc ibed by a ec o o 26 ea u es ha co espond
o he p obabili ies o belonging o any o he 26 subpopu-
la ions o 1000 genomes. Then, a machine lea ning bina y
classi ica o y was buil using a well-known a ian o he
g adien boos ing machine: ex eme g adien boos ing (XG-
Boos )(40) (see Supplemen a y Me hods o de ails).
Tes ing sample kinship and ou lie sample de ec ion
A es o de e mine undesi ed samples based on hei pe -
cen age o no el a ian s in oduced in he da abase, ei he
by excess (po en ial noisy sample) o by de ec (close el-
a i e o indi idual al eady in he da abase), has also been
used o popula e he CSVS da abase. A lea e-one-ou c oss-
alida ion (LOOCV) s a egy was o build a dis ibu ion o
pe cen ages o a ian s con ibu ed by any single sample o
he pool o a ian s p esen in he es o he da abase. Sam-
ples we e conside ed po en ial ou lie s i o e pass 1.5 imes
he in e qua ile ange om i s and hi d qua ile in he
dis ibu ion ob ained (see Supplemen a y Me hods o de-
ails).
Cons uc ion o he e e ence impu a ion panel
Two al e na i e e e ence panels we e c ea ed o compa -
ison pu poses ha include he CSVS WGS a ian panel
composed o 228 samples plus: (i) he en i e 1000G e e -
ence panel (CSVS+1000G) and (ii) exclusi ely he Span-
ish popula ion (IBS subpopula ion) con ained in he 1000G
panel (CSVS+IBS), using he Minimac3 impu a ion ool
(41). The ou longes ch omosomes (ch omosome 1–4)
we e used o es ima e he co ela ion be ween eal and im-
pu ed geno ypes ( 2pa ame e ) and assess he impu a ion
accu acy (see Supplemen a y Me hods o de ails).
RESULTS
The CSVS da abase
Figu e 1A shows how da a con ibu ed by di e en ge-
nomic p ojec s unde go di e en quali y con ol s eps, in-
cluding an a i ac and kinship de ec ion es s and local-
i y es , desc ibed abo e. Then he o iginal VCFs a e ag-
g ega ed as coun s o a ian s, binned by ICD10 (h ps:
//www.icd10da a.com/) disease ca ego ies, and inse ed in
he CSVS da abase.
The CSVS in e ace
The ini ial sc een (Figu e 1B) equi es he accep-
ance o he ‘Te ms and condi ions o he use o he
CSVS da abase’ (h p://cs s.babelomics.o g/downloads/
CSVSTe msAndCondi ions use.pd ) be o e s a ing any
ope a ion. Once accep ed, di e en op ions can be used.
The sea ch op ion. This is he main op ion and allows
que ying he CSVS da abase. In he le panel (Figu e 1C)
que ies can be done by gene symbol o by ch omosomal
egions. Also, one o se e al disease ca ego ies can be ex-
cluded, and a ian s can be highligh ed using di e en ypes
o sco es (e.g. SIFT (42), Polyphen (43), CADD (44), Ge p
(45)) as well as Sequence On ology e ms o he a ia ion
consequences.
The esul s o he que y (Figu e 1D) include a lis o he
posi ions o which a ia ion has been ound in he Span-
ish popula ion along wi h complemen a y da a as: ch omo-
some, posi ion, e e ence allele and al e na i e allele, allelic
equencies in he Spanish popula ion, allelic equencies in
he 1000 genomes popula ions and in he EVS popula ions,
impac and conse a ion indexes (SIFT, Polyphen, CADD,
Ge p), he wo o he consequence ypes assigned o he
mu a ion and he pheno ypes, co esponding o known clin-
ical in o ma ion o he a ian s, ex ac ed om ClinVa
(46), COSMIC (47) and a e anno a ed in e ac i ely on each
que y using he CellBase (48) webse ices. Also a isualiza-
ion o he a ian in he genomic con ex is p o ided, based
on he Genome Maps b owse (49). Addi ionally, some ex-
a de ailed in o ma ion can be ound on he popula ion e-
quencies obse ed o he a ian , he pheno ype o he e -
ec .
Con ac eques . An in e es ing op ion is he Con ac e-
ques bu on, o e ed o any a ian in he que y esul s
panel, which is a local equi alen o a Ma chmake ex-
change se ice (50), ex ensi ely used o con ac he o iginal
con ibu o o a speci ic sequence.
Sa u a ion plo s. Sa u a ion plo s (Figu e 1F) p o ide an
in e es ing pe spec i e on he gene al conse a ion o he
gene s udied and, consequen ly on he possibili ies o dis-
co e ing new a ian s in o i . Genes highly cons ained o
change will sa u a e soon and a ela i ely low numbe o
indi iduals will cap u e mos o he ole a ed mu a ion he
gene can handle, while uncons ained genes will p esen a
s ill g owing slope, meaning ha he e a e s ill many a i-
an s ha can po en ially be disco e ed. Disco e ing a new
a ian in a sa u a ed gene (cons ained o change) can be
mo e ele an han he same inding in a non-sa u a ed gene
(uncons ained). Sa u a ion has a clea unc ional compo-
nen , ha can easily be e ealed by en ichmen analysis
o he genes anked by sa u a ion. Thus, when genes a e
anked by hei ela i e sa u a ion, en ichmen analysis us-
ing en ichR (51) shows how highly sa u a ed genes (con-
s ained) a e en iched in unc ional e ms ela ed o meio-
sis, cell signaling, p oli e a ion and homeos asis, while he
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Nucleic Acids Resea ch, 2021, Vol. 49, Da abase issue D1133
Figu e 1. (A) da a is con ibu ed by di e en genomic p ojec s and pass h ough di e en quali y con ol s eps including an a e ac and kinship es
( ha de ec s uppe ou lie s, wi h an unexpec ed high a io o p i a e a ian s, mos likely e o s, and lowe ou lie s, ha a e duplica es o close kinship
indi iduals) and locali y es be o e being inse ed in he da abase. (B) Ini ial CSVS page. (C) Que y panel in he Sea ch op ion. (D) Lis o a ian s ound
in he Spanish popula ion wi hin he selec ed egion along wi h complemen a y in o ma ion on impac , conse a ion, o he ’s popula ion equencies and
pheno ype. (E) genomic b owse ha displays he selec ed a ian in i s genomic con ex . (F) Sa u a ion plo . (G) Upda ed con en s o he da abase.
less sa u a ed (uncons ained) a e mo e ela ed o senso y
pe cep ion, immune esponse and simila unc ionali ies
(see Supplemen a y Resul s and Supplemen a y Figu e S1).
Figu e 2depic s how genes wi h high and low sa u a ion a e
dis ibu ed along he ch omosomes. In e es ingly, sex ch o-
mosomes seem o be en iched in low sa u a ed genes.
Downloads and s a is ics. Pa ial o o al downloads o he
agg ega ed da a a e possible upon he ecep ion o he co -
esponding da a download ag eemen duly signed.
The S a s op ion p o ides an upda ed iew o he con en
o he CSVS da abase.
The Spanish Genome Re e ence Panel (SGRP1.0)
Supplemen a y Figu e S2 shows he accu acy o he wo e -
e ence panels de i ed o impu a ion in he Spanish popula-
ion. Bo h e e ence panels including he CSVS WGS e e -
ence ou pe o med he 1000 genomes e e ence. The impu-
a ion accu acy inc eases when a ian s in a e si es we e in-
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D1134 Nucleic Acids Resea ch, 2021, Vol. 49, Da abase issue
Figu e 2. Ci cos plo showing he di e en genes wi h high sa u a ion (o ange) and low sa u a ion (g een) along he ch omosomes, which we e signi ican ly
en iched in unc ional e ms in Supplemen a y Figu e S1.
cluded (MAF >0.005). The mos ealis ic impu a ion panel
includes CSVS and he IBS popula ion o he 1000 genomes.
Va ian s o pha macogenomic in e es
In e indi idual gene ic a iabili y in genes in ol ed in d ug-
me abolizing enzymes and anspo e s ha e been linked
o di e ences in he e icacy and oxici y o many medica-
ions: Mo eo e , gene ic di e ences be ween human popu-
la ions a e becoming inc easingly ecognized as impo an
ac o s accoun ing o in e indi idual a ia ions in d ug e-
sponsi eness (52,53). App oxima ely one- i h o new d ugs
app o ed in he pas yea s demons a ed di e ences in e-
sponse ac oss e hnic g oups, leading o popula ion-speci ic
p esc ibing ecommenda ions (54). In spi e o he consen-
sus abou he exis ence o a ela i e homogenei y wi hin
Eu opean popula ions, popula ion-speci ic di e ences in
he Spanish popula ion we e ecen ly epo ed (23). Using
he indi iduals o he CSVS eposi o y, we add essed how
popula ion-speci ic di e ences in hose genes in ol ed in
d ug Abso p ion, Dis ibu ion, Me abolism, Exc e ion and
Toxici y (ADMET) could a ec in he a es and isks o
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Nucleic Acids Resea ch, 2021, Vol. 49, Da abase issue D1135
d ug ine icacy and/o ad e se d ug eac ions in he Span-
ish popula ion. We es ima ed he allele equencies o a o-
al o 142 pha macogene ic a ian s desc ibed in he Pha -
mGKB da abase (55) wi h pha macogene ic clinical ecom-
menda ions (Pha mGKB a ian s le el 1A and 1B) and a
o al o 40 o hese we e ound o be polymo phic in he
CSVS. When compa ed wi h he allele equencies calcu-
la ed om gene ic da a o 30 000 Eu opean non-Finnish
indi iduals (gnomAD (56)), no ele an equency di e -
ences be ween he gene al Eu opean popula ion and he
Spanish popula ion we e obse ed, being he mos di e -
en s2228001 (le el 1B) in XPC gene, s2108622 (le el 1A)
in CYP4F2 gene and s3892097 (le el 1A) In CYP2D6 gene
(P- alue ≤1×10−10). Rega ding he non-polymo phic
a ian s, we obse ed ha all o hem a e low- equency
a ian s (lowe han 0.00065) and we do no expec o ind a
he e ozygous indi idual due o he sample size in ou epos-
i o y (Supplemen a y Table S1).
Apa om he gene ic a ian s al eady ecommended o
be implemen ed in he clinical se ing, i was ound ha ge-
ne ic a iabili y wi h unc ional impac was go e ned by
ew high- equency a ian s o some genes, bu he unc-
ionali y o he majo i y o pha macogenes is domina ed
by a e gene ic a ian s (57). In addi ion, local a iabil-
i y in hese ADMET genes could also be e y ele an
o explaining a subs an ial pa o he unexplained in e -
indi idual di e ences in d ug esponse and oxici ies a
he popula ion-speci ic le el, so ha i is manda o y o
ha e a ailable popula ion-speci ic ca alogs o hese pha ma-
a ian s (mainly a e) o explo e hei con ibu ion o p e-
dic ions o d ug esponse. To examine his, we s udied he
a iabili y o he Spanish popula ion cap u ed by ou epos-
i o y in a o al o 421 well-known pha macogenes in ol ed
in d ug pha macokine ics and/o d ug esponse (Supple-
men a y Table S2). High-impac a ian s wi hin hose pha -
macogenes we e de ined acco ding o he Va ian E ec
P edic o (58) as hose ha ing ha ing he ollowing con-
sequence ypes: ameshi , splice accep o , splice dono ,
s a los , s op gained, s op los , ansc ip abla ion and
ansc ip ampli ica ion. Addi ionally, dele e ious missense
a ian s ca ego ized as dele e ious by CONDEL (59)o
ha ing a LoF ool sco e (60) lowe han he i s qua ile co -
esponding o he mos in ole an a ian s.
As be o e, he same compa ison wi h he co espond-
ing Eu opean non-Finnish a ian s ende ed a o al o 318
high impac a ian s and 235 likely dele e ious missense sin-
gle nucleo ide a ian s in he pha macogenes s udied. In-
e es ingly, 18 (5.6%) high impac a ian s and 18 (7.6%)
missense a ian s iden i ied we e p esen in ou Spanish
popula ion while no he e ozygo es we e obse ed in hese
posi ions ac oss ∼30 000 heal hy indi iduals o he Eu o-
pean non-Finnish popula ion. Also, a non-negligible pe -
cen age o p i a e a ia ion was obse ed in hese genes
encoding p o eins in ol ed in d ug me abolism, anspo ,
and esponse, and his in o ma ion can be used o pin-
poin ele an p i a e gene ic a ian s o be included in he
design o popula ion-speci ic pha macogene ic geno yping
a ays o be u ilized in he implemen a ion o pha maco-
gene ic diagnos ics in he clinical se ing (Supplemen a y
Table S3).
CSVS Beacon
Since 2017, CSVS makes i s genomic in o ma ion disco e -
able h ough he GA4GH Beacon ne wo k (h ps://beacon-
ne wo k.o g/). In o de o imp o e he pe o mance o he
CSVS Beacon API we se up an SQLi e da abase speci ic o
his pu pose. Al hough CSVS s o es da a in 1-base i can e-
spond o que ies in bo h 1-base o 0-base (Beacon eques s
da a in 0-base). A o m o di ec ly make Bacon-s yle que ies
is also a ailable (h p://ucscbeacon.clinbioin osspa.es/).
DISCUSSION
The gene ic a iabili y o he local popula ion is ecognized
as one o he mos ele an ac o s in he disco e y o new
disease a ian s, especially in mendelian diseases (6,8,23).
Howe e , genomic da a o heal hy indi iduals belonging
o he local popula ion o in e es a e o en sca ce when
no una ailable. The CSVS p o ides an o iginal solu ion o
his p oblem. The CSVS is a con inuously g owing esou ce
ha collec s genomic o exomic sequences o he Span-
ish local popula ion, no ma e whe he hese come om
heal hy o diseased indi iduals. The main objec i e is us-
ing he eposi o y as a pseudo-con ol popula ion o ind-
ing new disease-causing a ian s and genes, wi h he idea
ha ‘disease A is a heal hy con ol o disease B’. Despi e
gene pleio opy canno be comple ely uled ou , da a a e
binned a highe disease ICD10 ca ego ies, whe e his gene
p ope y can be conside ed negligible. Ac ually, esou ces
like Disgene (61) can be used in case o doub , and will
be inco po a ed o au oma ically exclude he p ope disease
ca ego ies, in u u e CSVS e sions. Since he collec ion o
popula ion-speci ic genomic da a om indi iduals wi h di -
e en diseases a e easie o collec han hose om heal hy
dono s, CSVS p o ides an example o he cons uc ion o
popula ion-speci ic pseudo-con ol eposi o ies by means
o c owdsou cing (31). Mo eo e , he CSVS Beacon and he
Con ac eques op ion makes o CSVS a ool wi h high po-
en ial o disco e abili y. Thus, CSVS se s he g ound and i
is an example o u u e ede a ed Eu opean in as uc u es
(62).
DATA AVAILABILITY
CSVS is an open esou ce a ailable a h p://cs s.
babelomics.o g/.
The CSVS code, as well as he code o he di e en es s
used is a ailable in he co esponding gi hub eposi o y:
h ps://gi hub.com/babelomics/CSVS.
SUPPLEMENTARY DATA
Supplemen a y Da a a e a ailable a NAR Online.
ACKNOWLEDGEMENTS
The Spanish Exome C owdsou cing Conso ium is a de
ac o conso ium cu en ly composed by: F´
a ima Al-
Shah ou , Ra ael A uch, Ja ie Beni ez, Luis An onio
Cas a˜
no, Ignacio del Cas illo, Ai o Delmi o, Ca mina
Espinos, Rose Gonz´
alez, Daniel G inbe g, Enca naci´
on
Downloaded om h ps://academic.oup.com/na /a icle/49/D1/D1130/5912819 by Uni e sidad de Se illa use on 08 Sep embe 2022
D1136 Nucleic Acids Resea ch, 2021, Vol. 49, Da abase issue
Guill´
en, Pablo Lapunzina, Es he Lopez, Ram´
on Ma ´
ı,
Mon se a Mil´
a, Jos´
eMªMill´
an, Vi ginia Nunes, F ancesc
Palau, Belen Pe ez, Luis P´
e ez Ju ado, Rosa io Pe ona, Au-
o a Pujol, Feliciano Ramos, An onia Ribes, Jo di Rosell,
Eulalia Ro i a, Jo di Su all´
es, Isabel Tejada and Mag-
dalena Uga e.
FUNDING
Spanish Minis y o Economy and Compe i i eness
[SAF2017-88908-R, PT17/0009/0006 o J.D.; PI19/00321
and CIBERER ACCI-06/07/0036 o C.A., PI14-948, PI17-
1659 and CIBERER ACCI-06/07/0036 o M.A.M.P.];
Regional Go e nmen o Mad id, RAREGenomics-
CM [B2017/BMD-3721 o C.A. and B2017/BMD3721
o M.A.M.P.]; all co- unded wi h Eu opean Regional
De elopmen Funds (ERDF) as well as EU H2020-
INFRADEV-1-2015-1 ELIXIR-EXCELERATE [676559];
Uni e si y Chai UAM-IIS-FJD o Genomic Medicine
and he Ramon A eces Founda ion also suppo ed his
wo k. Funding o open access cha ge: Spanish Minis y
o Economy and Compe i i eness [SAF2017-88908-R].
Con lic o in e es s a emen . None decla ed.
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