HispanicCommunityHealthStudy/StudyofLatinos(HCHS- SOL)

NationalHeart,Lung,andBloodInstituteNationalInstituteofDiabetesandDigestiveandKidneyDiseases

NationalInstituteofNeurologicalDisordersandStrokeNationalInstituteofDeafnessandOtherCommunicationDisorders

NationalInstituteofDentalandCraniofacialResearchNationalInstituteforMinorityHealthandHealthDisparities

OfficeofDietarySupplements

ChallengestoHealthDisparitiesResearch

• Barriers– LegalStatus– PastTraumas–Discrimination–Marginalization–DistrustofGovernment– CulturalorLinguisticDifferences

2(USC, Center for Health Journalism)

Hispanic/LatinoDefined

Jaimes, Londono, Halpern, JAMA Dermatol, 2013

A- Latino refers to persons whose origin or ancestries are from countries of Latin America.

B-The US Office of Management and Budget uses the terms Hispanic and Latino interchangeably to refer to persons who indicated that their origin is Mexican, Puerto Rican, Cuban, Central and South American, or other Spanishculture or Spanish-speaking country or origin, regardless of race.

C-Hispanic include individuals whose origin or ancestry comes from Hispania, or D-Spanish-speaking persons of Latin American descent living in the United States.

3

GrowthanddiversificationofUSLatinopopulation

USHispanic/Latinos

1980 1990

2000 2010Pew Hispanic Center (www.pewhispanic.org)

5

HCHS- SOLcohortoverview• Multicenterprospectivecohortrecruitedin2008-2011

• N=16,415participantsaged18to74yearsold1/3ofparticipantswere18-45yearsatbaseline (undersampled)2/3ofparticipantswere>45yrs atbaseline(oversampled)AreabasedhouseholdsampleinfourUScities

• TOPMed contactPIs:RobertKaplanandKariNorth• GeneticSIGchairs:K.North,E.Boerwinkle,T.Sofer• GeneticAnalysisCenter:BruceWeirandCathyLaurie• OthersitePIs:M.Daviglus (Chicago),N.Schneiderman (Miami),G.Talavera(SanDiego),J.Cai(CC)

• SpirometryreadingcenterPIs:GrahamBarr,PaulEnright,JohnHankinson

RecruitmentN=16,415,ages

18-74

Annualfollow-upinterviewstodetermineoutcomesandchangesinkeyexposures2009-

2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

Secondclinicvisit2014-2017

Baselineclinicvisit2008-2011

StudyTimeline

Diseaseandbiometricphenotypes• Prevalent and incident pulmonary diagnoses + exacerbations• Pulmonary Function Testing (basal and post-bronchodilator)• Mortality (total and cause-specific)• Prevalent and incident CVD (MI, stroke, heart failure)•Anthropometry/Weight loss/gain • Lab values: lipids, glucose, OGTT, insulin, inflammation, CBC, Hepatitis A, B C, Total and HDL cholesterol, LFT, renal, etc• Oral/dental health• Pregnancy complications•Hearing • Blood pressure, ECG, echocardiography• Sleep quality and disorders • Cognitive Function• Substance Abuse • Diabetes• Health behaviors (smoking, diet, physical activity, etc)

StudyPopulation

Miami,FL

Chicago,IL

SanDiego,CA

Bronx,NY

9

• HispanicCommunityHealthStudy/StudyofLatinos(HCHS/SOL)– Community-basedstudyof16,415menandwomen,18-76yearsofageatbaselineexamination(2008-2011)

– Complexsamplingdesign– Self-identifiedas

• CentralAmerican• Cuban• Dominican• Mexican• PuertoRican• SouthAmerican• Other/Multiple

Pew Hispanic Center (www.pewhispanic.org)

4outof5cohortmemberswerebornoutsideofthe50states

Lengthoftimelivinginthe50statesondateofenrollment

DemographicCharacteristics

All Cuba Domin.Republic

Mexico PuertoRico

Cent.Amer.

So.Amer.

N 16,415 2,201 1,400 6,232 2,590 1,634 1,022

Men,% 40 46 34 37 41 39 40

College,% 15 20 15 12 14 14 22

Income>$50K,% 11 8 7 14 14 7 11

PreferSpanish,% 77 91 80 81 42 89 89

USresidence<10years,% 31 55 27 27 8 38 47

Daviglus ML JAMA 2012

Asthmaprevalence

Mexican PuertoRican

Cuban CentralAmerican

Dominican SouthAmerican

Physician-diagnosedasthma,ever

7.8(6.8–8.9)

30.9(27.8–34)

23.3(21.1–25.7)

12.8(10.7–15)

15.7(13.0–18.7)

10.4(7.9–13.5)

Physician-diagnosedasthma,current

3.4(2.7–4.1)

15.3(13.2–17)

8.6(7.1–10.4)

4.5(3.4–6.0)

6.7(5.3–8.5)

4.3(2.9–6.2)

AsthmaprevalenceishighestinLatinoswhocametothe50statesduringearlychildhood

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Estimated prevalence of asthma by age immigrated to US

Age immigrated to US

Prev

alenc

e of

ever

asth

ma

diagn

osed

by M

D

●

0

10

20

30

40

50

60%

1 5 10 15 20 25 30 35 40 45 50 55 60 65 70US

born

Note: Prevalence estimates and 95% confidence intervals are from a survey data logistic regression model with effects for age(continuous), sex, Hispanic background, and age at immigration (grouped into 65 categories)

GrahamBarrAmJRespir Crit CareMed 2015

+

ElinaJerschow AmericanJournalofPreventiveMedicine2017

ElinaJerschow AmericanJournalofPreventiveMedicine2017

SOLGeneticProjects

• Omics inLatinos(OLa)GWAS

• PAGEconsortium– Metabochip– MEGAchip

• Wholegenomesequencing

16

SOLGeneticProjects

• Omics inLatinos(OLa)GWAS

• PAGEconsortium– Metabochip– MEGAchip

• Wholegenomesequencing

17

OLa GWASProjectSNPMicroarrayData

12,803studyparticipantsprovidedconsentforgeneticstudies

Illumina Omni2.5M+~150kcustomcontent‘SoL_HCHS_Custom_15041502_B’

Arraydesign– Papanicolaou(NHLBI),RotterandTaylor(LABiomed)

GenotypingperformedbyIllumina &QCbyLABiomed

QAbySOLGeneticAnalysisCenter(Univ.Washington)

Imputationto1000Gphase3

18

AnkleBrachialIndex Dental

Anthropometrics Diabetes

Anxiety/Depression Electrocardiography

BloodCellCount PulmonaryDisease

BloodPressure Sleep

ChronicKidneyDisease mtDNA/YChr

Lipids Reproductivetraits

Smoking

19

SOLGeneticAnalysisWorkingGroups

www.olgastudy.org

20ScrolldownforallworkinggroupsandtheirmembersDirectoryhascontactinformation

1.EstimaterelatednessusingKING-robust,whichisrobusttodiscretepopulationstructurebutnottoadmixtureordeparturesfromHWEwithinsub-populations.

2.Partitionthesampleintoamutuallyunrelatedsetandtheremaining(relativesoftheunrelatedsetandpossiblyeachother)

3.Performstandardprincipalcomponentsanalysis(PCA)onthesetofunrelatedindividualsandprojectontorelatedindividuals

4.Re-estimaterelatednessusing‘PC-Relate’,whichprovidesunbiasedkinshipcoefficientsinthepresenceofpopulationstructure,admixtureandHWEdepartures,usingindividual-specificallelefrequenciesestimatedfromsampleeigenvectors.

5.Repeatsteps2-5togetfinalsetsofeigenvectorsandkinshipcoefficients

De-convolutionofancestryandrelatednessinadmixedpopulationsMattConomos andTimThornton(UniversityofWashington)

21

GeneticAnalysisIssues1. Tieredconsentallowsvariablelevelsofdatasharing.Reconsentingat

eachinpersonvisitmaynecessitatewithdrawalofsubjects

1. Samplesurveydesign,2-stageprobabilitysamplinga. Primarysamplingunit=UScensusblockgroupb. Secondarysamplingunit=householdc. Householdbasedsampling(average1.8enrolledperHH)

2. Relatedness,populationstructureandadmixturea. ~85%ofsubjectsaremutuallyunrelatedb. ~15%areeachrelatedtosomeoneintheunrelatedsetc. SOLparticipantsareverydiverseethnicallyandgenetically

i. Caribbeangroups:Cuban,Dominican,PuertoRicanii. Mainlandgroups:Mexico,CentralAmerica,SouthAmerica

d. Novelmethodusedtode-convoluteancestryandrelatedness(Conomos &Thornton)

MixedmodelandGEEapproacheshavebeendevelopedtohandletheseissuesinassociationtests(GWAS).BothcontrolTypeIerrorwell,butmixedmodelhasmorepower.(Mixedmodel– Conomos +Thornton;GEE- Lin+Tao)

Populationstructure

Principalcomponentsanalysis(PCA)

Conomos 2016.

PCAplots(EV1-3)

Proportionofancestralbackgrounds

Conomos etal.2016.

ContinentalancestryproportionsestimatedusingADMIXTUREsoftwareAutosomal

Xchromosome

SeparatePCAforeachofthe3ancestries

HCHS-SOLgroups

Referencepopulations

SharonBrowningG32016

SeparateclusteringofAfricancomponentofHondurans/Guatemalans

• Garífuna population.

• MayhaveancestryfromspecificpartsofAfrica.

• Ordriftduetosmallpopulationsize.

HCHS-SOLgroups

Referencepopulations

Africa

SharonBrowningG32016

ThreedistinctAmerindianclusters

• Mexico,CentralAmerica,SouthAmerica.

HCHS-SOLgroups

Referencepopulations

Americas

SharonBrowningG32016

SeparateclusteringofEuropeancomponentofPuertoRicans

• MayincludeancestryfromNorthAfricanorMiddleEast.

• Ordriftduetosmallpopulationsize.

HCHS-SOLgroups

Referencepopulations

Europe

SharonBrowningG32016

Eachofthefirst5Eigenvectorsdifferentiatesamongself-identifiedgroups

• Usethese5eigenvectorstoadjustforancestryinassociationtestsandtodefinegeneticanalysisgroupsforstratifiedanalysis• Comparedwithself-identifiedbackground(personalorfamilyplaceoforigin),thegroupsaremorehomogeneousgeneticallyandincludeindividualswithmissingor“other”self-identification 31

SOLGeneticProjects

• Omics inLatinos(OLa)GWAS

• PAGEconsortium– Metabochip– MEGAchip

• Wholegenomesequencing

32

KariNorthUNC-CH

CALiCOConsortium

PopulationArchitectureusingGenomicsandEpidemiology(PAGE)Study

RuthLoosMountSinaiSchoolofMedicine

MSSMBiobank

TaraMatiseRutgersUniversity

CoordinatingCenterCharlesKooperbergFHCRC

Women’sHealthInitiative

ChrisHaimanUSC

MultiethnicCohortStudy

33

ThePAGEStudyPopulationArchitectureusingGenomicsandEpidemiologyIINetwork

• Goal:Investigateancestrallydiversepopulationstogainabetterunderstandingofhowgeneticfactorsinfluencesusceptibilitytodisease.

• FocusonUSminoritypopulations.

17,328

4,696

22,250

653

3,944

1,056

African-American

Asian

Hispanic/Latino

NativeAmerican

NativeHawaiian

Others

ILLUMINA ARRAY SEMINAR, SEPTEMBER 2016

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Common Low Frequency Rare

AAC

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0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0.4, 0

.5

0.3, 0

.4

0.2, 0

.3

0.1, 0

.2

0.5, 0

.1

0.04,

0.05

0.03,

0.04

0.02,

0.03

0.01,

0.02

0.005

, 0.01

Variant Frequency

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tatio

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cura

cy, M

ean

r2

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Omni1MOmniExpressAxiom.AFRMEGA

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Common Low Frequency Rare

AFR

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0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0.4, 0

.5

0.3, 0

.4

0.2, 0

.3

0.1, 0

.2

0.5, 0

.1

0.04,

0.05

0.03,

0.04

0.02,

0.03

0.01,

0.02

0.005

, 0.01

Variant FrequencyIm

puta

tion

Accu

racy

, Mea

n r2

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Omni1MOmniExpressAxiom.AFRMEGA

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Common Low Frequency Rare

AMR

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0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0.4, 0

.5

0.3, 0

.4

0.2, 0

.3

0.1, 0

.2

0.5, 0

.1

0.04,

0.05

0.03,

0.04

0.02,

0.03

0.01,

0.02

0.005

, 0.01

Variant Frequency

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tatio

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cy, M

ean

r2

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Omni1MOmniExpressAxiom.LATMEGA

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Common Low Frequency Rare

SAS

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0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0.4, 0

.5

0.3, 0

.4

0.2, 0

.3

0.1, 0

.2

0.5, 0

.1

0.04,

0.05

0.03,

0.04

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0.03

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0.005

, 0.01

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Omni1MOmniExpressAxiom.EASMEGA

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Common Low Frequency Rare

EAS

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0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0.4, 0

.5

0.3, 0

.4

0.2, 0

.3

0.1, 0

.2

0.5, 0

.1

0.04,

0.05

0.03,

0.04

0.02,

0.03

0.01,

0.02

0.005

, 0.01

Variant Frequency

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tatio

n Ac

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cy, M

ean

r2

Array●

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Omni1MOmniExpressAxiom.EASMEGA

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Common Low Frequency Rare

EUR

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0.2

0.3

0.4

0.5

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0.7

0.8

0.9

1.0

0.4, 0

.5

0.3, 0

.4

0.2, 0

.3

0.1, 0

.2

0.5, 0

.1

0.04,

0.05

0.03,

0.04

0.02,

0.03

0.01,

0.02

0.005

, 0.01

Variant Frequency

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tatio

n Ac

cura

cy, M

ean

r2

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Omni1MOmniExpressAxiom.EURMEGA

ComparisonofMEGAImputationAccuracytoOtherCommercialChips(SupplementaryFigure)

SOLGeneticProjects

• Omics inLatinos(OLa)GWAS

• PAGEconsortium– Metabochip– MEGAchip

• Wholegenomesequencing

36

HCHS/SOLsampleselectionforwholegenomesequencingN=1917asthmacases(everdiagnosedbyaphysician)N=4503controls(neverdiagnosedbyaphysician)

NHGRI/PAGE ~270samplesselectedforhighAmerindianancestryPrimarilyCentralandSouthAmerican(onlyonePuertoRican)WashingtonU.sequencingcenter

NHGRI/CCDG ~4000samplesselectedatrandom Baylorsequencingcenter

TOPMed Totalapprovedallocationof2150 Baylorsequencingcenter1. Allever-asthmacasesnotpreviouslyselectedbyPAGEorCCDG,N=1277.(Bringing

totalofever-asthmacasesto1917acrossallthreesampleselections)

2. SixsamplespreviouslyselectedbyPAGE,whichwillserveascross-sequencingcentercontrols(onepergeneticanalysisgroupe.g.Cuban,Mexican,Dominican,etc),N=6

3. RemainingPuertoRicansnotincludedinPAGEorCCDGselections,N=867.

WethanktheparticipantsandstaffoftheHispanicCommunityHealthStudy/StudyofLatinos(HCHS/SOL)fortheircontributionstothisstudy.ThebaselineexaminationofHCHS/SOLwascarriedoutasacollaborativestudysupportedbycontractsfromtheNHLBItotheUniversityofNorthCarolina(N01-HC65233),UniversityofMiami(N01-HC65234),AlbertEinsteinCollegeofMedicine(N01-HC65235),NorthwesternUniversity(N01-HC65236),andSanDiegoStateUniversity(N01-HC65237).Thefollowinginstitutes,centers,andofficescontributedtothefirstphaseofHCHS/SOLthroughatransferoffundstotheNHLBI:NationalInstituteonMinorityHealthandHealthDisparities,NationalInstituteonDeafnessandOtherCommunicationDisorders,NationalInstituteofDentalandCraniofacialResearch(NIDCR),NationalInstituteofDiabetesandDigestiveandKidneyDiseases(NIDDK),NationalInstituteofNeurologicalDisordersandStroke,andNIHOfficeof DietarySupplements.TheGeneticAnalysisCenterattheUniversityofWashingtonwassupportedbyNHLBI andNIDCRcontracts(HHSN268201300005CAM03and MOD03).Additional analysissupportwasprovidedby1R01DK101855-01and13GRNT16490017.GenotypingeffortsweresupportedbytheNIHDepartmentofHealthandHumanServices(HSN26220/20054C),NationalCenterforAdvancingTranslationalScienceClinicalTranslationalScienceInstitute(UL1TR000124),andNIDDKDiabetesResearchCenter(DK063491).