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Advances in the Genetics of ADHD

Stephen V. Faraone, Ph.D.

Departments of Psychiatry & of Neuroscience and Physiology SUNY Upstate Medical University @StephenFaraone

www.mghcme.org

Financial Disclosures (Past 2 Years) Source Research or

CME Funding

Consult Fees

Speakers Bureau

Royalties or IP

Travel Stock/Equity Honorarium or expenses for this meeting

NHE Inhibitor Patent X

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0 0.2 0.4 0.6 0.8 1 1.2

Matheny 1971Willerman 1973Goodman 1989

Gillis 1992Edelbrock 1992Stevenson 1992

Schmitz 1995Thapar 1995Gjone 1996

Silberg 1996Sherman 1997

Levy 1997Nadder 1998

Hudziak 2000Willcutt 2000Thapar 2000

Coolidge 2000Kuntsi 2001

Martin 2002Rietveld 2003Laarson 2004

Dick 2004Derks 2007

Polderman 2007Spatola 2007

Cole 2009Bornovalova 2010

Illott 2010Anckarsater 2011

Langner 2013Chang 2013

Heritability

Mean =.74

Heritability of ADHD Measures in Youth (Faraone & Mick, Psych Clin N. Am, 2010)

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0 0.2 0.4 0.6 0.8 1

Parent Ratings

Teacher Ratings

Self Ratings

Heritability

ADHD in Youth

Heritability of ADHD Symptoms (SDQ) in

Adolescence (Merwood et al., Psych Med, 2013)

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0 0.2 0.4 0.6 0.8 1

Parent Ratings

Self Ratings

Heritability

ADHD in Youth

Heritability of ADHD Symptoms in Adults (Chang et al., JAMA Psych, 2013)

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Developmental Heritability of Attention Problems (Chang et al., JAMA Psych, 2013)

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Childhood ADHD is Extreme of Quantitative Trait in 8,500

Twin Pairs (Larsson et al., JCPP, 2012)

Significant group heritability indicates genetic link between the extreme and sub-threshold ranges of ADHD symptoms. Which is robust to how ‘extreme’ is defined

0 0.2 0.4 0.6 0.8 1

Broad ScreeningCriteria

Strict DiagnosticCriteria

Heritability

95%CI: .54–.66

95%CI: .52–.76

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The PGC ADHD/iPSYCH-SSI-Broad collaboration 106 Members, 14 Countries, 5 Continents

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Abel Ickowitz

Aisling Mulligan

Alejandro Arias Vasquez

Alexandre Todorov

Alice Charach

Alysa Doyle

Amaia Hervas

Ana Miranda

Anders Børglum

Andre Scherag

Andreas Reif

Andreas Warnke

Anita Thapar

Anke Hinney

Anna-Lena Volckmar

Aribert Rothenberger

Astrid Dempfle

Barbara Franke

Beate Herpertz-Dahlmann

Benjamin Neale

Benno G. Schimmelman

Beth Wilmot

Bru Cormand

Carol Matthews

Christine Freitag

Christina Sanchez-Mora

Claiton Bau

Ditte Demontis

Edmund Sonuga-Barke

Eric Mick

Esther Sobanski

Fernando Mulas

Gerd Lehmkuhl

Hakon Hakonarson

Hans-Christoph Steinhausen

Haukur Palmason

Helmut Schäfer

Herbert Roeyers

Irwin Waldman

James McGough

Jan Buitelaar

Jan Haavik

Jasmin Romanos

Jennifer Crosbie

Jonna Kuntsi

Jobst Meyer

Joel Gelernter

Joel Nigg

Joanna Martin

Johannes Hebebrand

Josep Antoni Ramos-Quiroga

Joseph Biederman

Joseph Sergeant

Josephine Elia

Judith Sinzig

Kate Langley

Klaus-Peter Lesch

Li Yang

Lindsey Kent

Luis Rhode

Mara Hutz

Marcel Romanos

Marcella Rietschel

Margaret Thompson

Maria Jesus Arranz

Mark Daly

Marta Ribases

Michael Gill

Michael O’Donovan

Michael Owen

Miguel Casas

Molly Nikolas

Nanda Lambregts-Rommelse

Nigel Williams

Nina Roth Mota

Olga Rivero

Özgür Albayrak

Peter Holmans

Philip Asherson

Preben Bo Mortensen

Raymond Walters

Richard JL Anney

Richard P. Ebstein

Robert D. Oades

Russell Schachar

Sandra Loo

Sarah Hohmann

Sarah Medland

Sharon McWeeney

Stan Nelson

Stefan Johansson

Stephan Ripke

Stephanie Witt

Susan Smalley

Susanne Walitza

Soren Dalsgaard

Stephen V. Faraone

Tetyana Zayats

Tobias Banaschewski

Tobias J. Renner

T Trang Nguyen

Yanli Zhang-James

Yufeng Wang

Acknowledgements: PGC Sample Collection

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iPSYCH

Ditte Demontis

Manuel Mattheisen

Jakob Grove

Jonatan Pallesen

Mads Hauberg

Thomas D. Als

Marianne G. Pedersen

Carsten B. Pedersen

Jonas Grauholm

Marie Bækvad-Hansen

Jesper B. Poulsen

Soren Dalsgaard

Mads V. Hollegaard

David M. Hougaard

Merete Nordentoft

Ole Mors

Thomas Werge

Preben Bo Mortensen

Anders Børglum

Broad Institute/MGH

Mark Daly

Ben Neale

Raymond Walters

Jackie Goldstein

Joanna Martin

Stephan Ripke

Jennifer Moran

Kim Chambert

Rich Belliveau

Ashley Dumont

Colm O’Dushlaine

Christine Stevens

Wendy Brodeur

George Grant

Diane Gage

Julian Maller

Felecia Cerrato

Funding

Many NIMH & European Union Grants

Lundbeck Foundation

Stanley Center for Psychiatric Research

Gerstner Family Foundation

Mount Sinai School of Medicine

Friedman Brain Institute

Acknowledgements: iPSYCH, Broad Institute/MGH and Funding Sources

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ADHD GWAS: 20,183 cases 35,191 controls, 8,151,190 genetic markers

12 genome-wide significant loci

12 genome-wide significant loci

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12 genome-wide significant loci (+2 possible independent secondary signals)

Top SNP CHR BP OR P Gene

rs11420276 1 44184192 1.11316 2.14E-13 ST3GAL3, KDM4A

rs1427829 12 89760744 1.08318 1.82E-09 DUSP6

rs212178 16 72578131 0.89101 7.68E-09 LINC01572

rs28411770 4 31151456 1.08992 1.15E-08 PCDH7, LOC102723778

rs11591402 10 106747354 0.91128 1.34E-08 SORCS3

rs74760947 8 34352610 0.83544 1.35E-08 -

rs9677504 2 215181889 1.12401 1.39E-08 SPAG16

rs4916723 5 87854395 0.92626 1.58E-08 LINC00461

rs5886709 7 114086133 1.07875 1.66E-08 FOXP2

rs4858241 3 20669071 1.0821 1.74E-08 -

rs281324 15 47754018 0.92821 2.68E-08 SEMA6D

rs1222063 1 96602440 1.10098 3.07E-08 -

rs3952787 1 44323244 1.0848 3.49E-08 ST3GAL3, MIR6079

rs304132 5 88215594 0.92459 4.23E-08 MEF2C

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Clinical Phenotypes Associated with FOXP2 Mutations (Bacon & Rappold, Human Genetics, 2012)

• Impaired speech production, grammar defects. articulatory impairment

• Abnormal activation in motor-related areas during word repetition (PET)

• Reduced volume and significantly less grey matter bilaterally in the caudate nucleus (MRI) in clinically referred samples but not in general population (Hoogman et al., 2014)

• Abnormal activation of Broca’s area and putamen (fMRI)

• Moderate intellectual disability

• Cognitive and motor developmental delays

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FOXP2 Brain Localization (IPA)

• striatum, cerebral cortex, cerebellar vermis, cerebellar nucleus, mesencephalon, substantia nigra, thalamus, ventral tegmental area, visual cortex layer VI

• cortical projection neurons, dopaminergic neurons, Purkinje cells, medium spiny neurons, pyramidal neurons

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FOXP2 Brain Localization (IPA)

• striatum, cerebral cortex, cerebellar vermis, cerebellar nucleus, mesencephalon, substantia nigra, thalamus, ventral tegmental area, visual cortex layer VI

• cortical projection neurons, dopaminergic neurons, Purkinje cells, medium spiny neurons, pyramidal neurons

FOXP2 codes for a transcription factor, which may bind directly to 300 to 400 gene promoters in the human genome

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Dopamine Levels in FOXP2 KO and ‘Humanized’ FOXP2 in Mice (Enard et al., Cell, 2009)

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Understanding Molecular Polygenic Risk Scores (Faraone, Biol Psychiat, 2014)

• A polygenic risk score indexes the number of ADHD risk alleles carried by an individual.

• Each risk allele or risk variant is the nucleotide that is more frequently observed among ADHD cases using an arbitrary (and typically liberal) level of statistical significance.

• Many of the variants comprising the polygenic score will be true risk variants but many will be false positives. It is the statistical significance of the polygenic score that assures us that it has captured many true positives in the mix.

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The Polygenic Score is a Molecular Genetic Tease (Faraone, Biol Psychiat, 2014)

• It confirms that many common DNA variants are associated with ADHD.

– But “many” could mean hundreds, thousands or more.

– It cannot tell us which variants are truly associated with the disorder.

• It can tell us that about 40 percent of ADHD’s heritability is due to common DNA variants.

– We can use polygenic scores to assess genetic overlap among disorders

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Genetic Correlations Between Samples

PGC+iPSYCH PGC

Only

iPSYCH

Only EAGLE 23&Me

PGC

+iPSYCH -- 1.226 (.244) 0.977 (.005) 0.943 (.221) 0.653 (.115)

PGC

Only 4.02E-14 -- 1.281 (.169) 0.974 (.313) 0.682 (.203)

iPSYCH

Only 0.00E+00 5.31E-07 -- 0.982 (.212) 0.609 (.107)

EAGLE 3.65E-06 1.87E-03 1.96E-05 -- 0.706 (.260)

23&Me 1.11E-08 7.81E-04 1.32E-08 6.73E-03 --

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ADHD Polygenic Risk Predicts Attention Problems in the Population

(Groen-Blokhuis et al., JAACAP, 2014)

Similar findings by Martin et al. Biol Psych (2013) & Stergiakouli et al., JAACAP (2015)

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Polygenic Risk and Conduct Disorder (Hamshere et al., AJP, 2013)

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Molecular Genetic Correlations with ADHD http://ldsc.broadinstitute.org

Trait Category Correlation SE P-value

Summary: Gene finding in ADHD (Faraone et al., Nature Rev Dis Primers, in press)

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Parsing the Etiology of ADHD

Environment & Error

Common SNPs

Rare Variants & G*E

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Clinical Implications of the Complex Etiology of ADHD

• Do complex disorders require a complex diagnostic system?

– Heterogeneity

– Dimensionality (RDoC)

– Comorbidity vs. Differential Diagnosis

• Do complex disorders require complex treatment?

– Multiple targets for drugs and naturopathic compounds

– Genetic Nihilism

– Environmental manipulations

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Thanks for Listening!

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My ADHD blogs: bit.ly/FaraoneBlogs