Selective Genetic Overlap Between Amyotrophic Lateral Sclerosis and Diseases of the Frontotemporal Dementia Spectrum

Supplementary Online Content

Karch CM, Wen N, Fan CC, et al; International Frontotemporal Dementia (FTD)– Genomics Consortium; International Collaboration for Frontotemporal Dementia; Progressive Supranuclear Palsy (PSP) Genetics Consortium; International Parkinson’s Disease Genomics Consortium. Selective genetic overlap between amyotrophic lateral sclerosis and diseases of the frontotemporal dementia spectrum. JAMA Neurol. Published online April 9, 2018. doi:10.1001/jamaneurol.2018.0372

eTable 1. Summary Data From GWAS Used in the Current Study eTable 2. ALS Risk SNPs Conditional on FTD, PSP, CBD, TDP43 at a Conditional FDR <0.05 eTable 3. eQTLs Reveal Functional Effects of Novel ALS Risk SNPs (From Conditional FDR Analysis) in a Human Brain Tissue (UKBEC) eTable 4. Gene-Based Analysis of Genes From Conjunction and Conditional FDR Analysis eTable 5. Pathway Analysis of Shared Risk Genes From Conjunction and Conditional FDR Analyses eTable 6. Differential Expression of Shared ALS-FTD Risk Genes in Diseased Central Nervous System Tissues eFigure 1. Conditional Manhattan Plots Reveal Novel Risk Loci eFigure 2. Genetic Enrichment Between ALS, Sporadic FTD, and FTD-TDP43 After Controlling for LD in chr 9 and chr 17 eFigure 3. Cell-Type Specific Expression of BNIP1 eAppendix 1. Methods eAppendix 2. Acknowledgments

This supplementary material has been provided by the authors to give readers additional information about their work.

eTable 1. Summary Data From GWAS Used in the Current Study

Disease Case Control Reference Van Rheenen W et al. Genome-wide association analyses identify new risk variants and the genetic ALS - Phase 1 12,577 23,475 architecture of amyotrophic lateral sclerosis. Nat Genet. 2016; 48: 1043-8. Lambert JC, et al. Meta-analysis of Alzheimer’s disease 74,046 individuals identifies 11 new 17,008 37,154 (AD) IGAP – Phase 1 susceptibility loci for Alzheimer's disease. Nat Genet. 2013;45:1452-8. Nalls MA et al. Imputation of sequence variants for identification Parkinson’s disease of genetic risks for Parkinson’s 5,333 12,019 (PD) disease: a meta-analysis of genome- wide association studies. Lancet. 2011:377;641-9. Van Deerlin VM, et al. Common variants at 7q21 are associated with TDP-43 515 2,509 frontotemporal lobar degeneration with TDP-43 inclusions. Nat Genet. 2010:42;234-9. Kouri N, et al. Genome-wide association study of corticobasal Corticobasal degeneration identifies risk variants degeneration (CBD) – 152* 3,311 shared with progressive Phase 1 supranuclear palsy. Nat Comm. 2015;6:7247. Höglinger GU, et al. Identification of Progressive common variants influencing risk of Supranuclear Palsy 1,114 3,247 the tauopathy progressive (PSP) – Phase 1 supranuclear palsy. Nat Genet. 2011:43:699-705. Ferrari, R et al. Frontotemporal Frontotemporal dementia and its subtypes: a Dementia (FTD) – 2,154 4,308 genome-wide association study. IFGC Phase 1 Lancet Neuro. 2014:13;686-99. *Autopsy-confirmed

Downloaded From: https://jamanetwork.com/ on 09/25/2021 eTable 2. ALS Risk SNPs Conditional on FTD, PSP, CBD, TDP43 at a Conditional FDR <0.05 Nearest Associated Min ALS SNP Chr Gene Phenotype Conj FDR p-value rs2068667 1 NFASC PSP 2.96E-02 3.47E-04 rs11185393 1 AMY1A TDP43 4.91E-02 1.38E-04 rs515342 2 ASB1 FTD 3.19E-02 6.13E-04 rs1768208 3 MOBP FTD/PSP 6.89E-03 4.04E-05 rs13079368 3 MOBP FTD 1.99E-03 4.11E-05 rs3828599 5 GPX3 PSP/CBD/FTD/TDP43 1.53E-02 2.51E-06 rs17111695 5 NAF1 TDP43 2.32E-03 1.98E-05 rs757651 5 REEP2 FTD 4.62E-02 8.04E-04 rs538622 5 ERGIC1 FTD 3.07E-02 1.37E-05 rs10488631 7 TNPO3 TDP43 5.00E-02 2.60E-05 rs7813314 8 BC045738 FTD 4.86E-03 7.78E-07 rs3849943 9 C9orf72 FTD 5.30E-09 4.56E-19 rs10511816 9 MOBKL2B TDP43 4.97E-09 6.08E-11 rs13302855 9 C9orf72 FTD 2.03E-04 4.04E-06 rs870901 9 AK097706 TDP43 4.67E-02 8.86E-04 rs732389 10 AK294518 FTD 4.54E-02 5.57E-04 rs7118388 11 CAT TDP43 4.24E-03 2.44E-06 rs12803540 11 CAT FTD 2.09E-02 9.72E-06 rs17446243 13 TTL/TEL FTD 4.30E-02 1.12E-05 rs10492593 13 PCDH9 FTD 3.97E-02 2.98E-05 rs1578303 13 HTR2A TDP43 4.72E-02 9.84E-05 rs12886280 14 NUBPL TDP43 3.81E-02 3.27E-06 rs6603044 15 BTBD1 FTD 1.44E-02 1.12E-05 rs739439 17 KIAA0524 FTD 6.17E-05 1.87E-08 rs7224296 17 NSF PSP 4.54E-02 5.90E-04 rs2285642 17 GGNBP2 FTD 4.15E-02 5.25E-06 rs2240601 17 MSI2 TDP43 1.44E-02 5.22E-05 rs12608932 19 UNC13A FTD 1.04E-06 1.83E-08 rs2425220 20 DLGAP4 FTD 2.50E-02 1.28E-04

Downloaded From: https://jamanetwork.com/ on 09/25/2021 eTable 3. eQTLs Reveal Functional Effects of Novel ALS Risk SNPs (From Conditional FDR Analysis) in a Human Brain Tissue (UKBEC) eQTL Nearest SNP Chr Gene P value Gene

rs2068667 1 NFASC 2.30E-03 NFASC rs11185393 1 AMY1A 1.20E-01 RNPC3,AMY2B rs515342 2 ASB1 4.50E-03 SCLY,UBE2F rs1768208 3 MOBP 2.30E-03 WDR48 rs13079368 3 MOBP 2.00E-04 SCN5A rs3828599 5 GPX3 5.80E-04 DCTN4 rs17111695 5 NAF1 7.30E-04 TNIP1 rs538622 5 ERGIC1 1.10E-03 BNIP1 rs10488631 7 TNPO3 7.60E-04 AHCYL2 rs7813314 8 BC045738 1.50E-02 ARHGEF10 rs3849943 9 C9orf72 4.80E-03 MOBKL2B rs10511816 9 MOBKL2B 2.00E-04 TEK rs13302855 9 C9orf72 1.30E-02 LRRC19 rs870901 9 AK097706 1.20E-04 ZNF462 rs732389 10 AK294518 1.10E-02 LOC100128292 rs7118388 11 CAT 1.40E-02 CD59,C11orf91 rs12803540 11 CAT 3.10E-03 CAT rs17446243 13 TTL/TEL 1.90E-03 SUGT1L1 rs10492593 13 PCDH9 1.80E-01 PCDH9 rs1578303 13 HTR2A 1.30E-02 SUCLA2 rs12886280 14 NUBPL 5.30E-03 AP4S1 rs6603044 15 BTBD1 7.20E-06 C15orf40 rs739439 17 KIAA0524 5.00E-04 POLDIP2,TNFAIP1 rs7224296 17 NSF 3.30E-18 KIAA1267 rs2285642 17 GGNBP2 7.30E-12 GGNBP2 rs2240601 17 MSI2 3.00E-03 CUEDC1 rs12608932 19 UNC13A 1.80E-03 HAUS8 rs2425220 20 DLGAP4 1.20E-04 C20orf24 Note: rs757651 not available.

Downloaded From: https://jamanetwork.com/ on 09/25/2021 eTable 4. Gene-Based Analysis of Genes From Conjunction and Conditional FDR Analysis

GO ID GO Term Gene Members FDR GO:0017075 Syntaxin-1 binding NSF; UNC13A 2.59E-06 GO:0000149 SNARE binding NSF; UNC13A 2.78E-04 GO:0048278 vesicle docking NSF; UNC13A 3.35E-04 GO:0034706 sodium channel complex SCN11A; SCN5A 1.46E-03 GO:0051648 vesicle localization NSF; UNC13A 2.17E-03 GO:0043209 myelin sheath SUCLA2; CD59; NFASC; MOBP; NFASC; NSF 2.28E-03 GO:0006887 exocytosis NSF; UNC13A 3.22E-03 GO:0016050 vesicle organization NSF; UNC13A 3.22E-03 GO:0051046 regulation of secretion NSF; UNC13A 3.90E-03 voltage-gated sodium GO:0001518 SCN11A; SCN5A 4.07E-03 channel complex GO:0015629 actin cytoskeleton TEK; ELL 5.45E-03 GO:0014854 response to inactivity SCN5A; CAT 5.65E-03 oxidoreductase activity, GO:0016684 acting on peroxide as GPX3; CAT 6.76E-03 acceptor GO:0019226 transmission of nerve impulse SCN11A; NFASC; SCN5A 9.05E-03 establishment of organelle GO:0051656 NSF; UNC13A 0.01 localization GO:0051640 organelle localization NSF; UNC13A 0.01 GO:0004601 peroxidase activity GPX3; CAT 0.01 PCDH9; AMY2A; AMY2B; NSF; CAT; HTR2A; GO:0043169 cation binding 0.01 NUBPL; UNC13A; AMY1A; AMY1C; AMY1B GO:0043198 dendritic shaft HTR2A; NSF 0.01 AMY2A; AMY2B; NFASC; NSF; CAT; GPX3; GO:1903561 extracellular vesicle 0.02 AMY1A; AMY1C; AMY1B GO:0005911 cell-cell junction PCDH9; NFASC; SCN5A; TEK 0.02 GO:0030055 cell-substrate junction TEK; NFASC; CD59; CAT 0.02 hydrogen peroxide catabolic GO:0042744 GPX3; CAT 0.02 process GO:0043005 neuron projection PCDH9; NFASC; HTR2A; NSF; UNC13A 0.02 PCDH9; AMY2A; AMY2B; NSF; CAT; NUBPL; GO:0046872 metal ion binding 0.02 UNC13A; AMY1A; AMY1C; AMY1B regulation of epithelial cell GO:0050678 WDR48; TEK 0.03 proliferation skeletal system GO:0048705 WDR48; TEK 0.03 morphogenesis GO:0070161 anchoring junction TEK; NFASC; CD59; CAT 0.03 GO:0005925 focal adhesion TEK; NFASC; CD59; CAT 0.03 regulation of phosphorus GO:0051174 TEK; ELL; LRRC19 0.03 metabolic process hydrogen peroxide metabolic GO:0042743 GPX3; CAT 0.04 process membrane depolarization GO:0086010 SCN11A; SCN5A 0.04 during action potential GO:0019228 neuronal action potential SCN11A; SCN5A 0.04 GO:0030424 axon NFASC; HTR2A; UNC13A 0.05

Downloaded From: https://jamanetwork.com/ on 09/25/2021 eTable 5. Pathway Analysis of Shared Risk Genes From Conjunction and Conditional FDR Analyses

Pathway Shared Risk Genes within Pathway FDR Synaptic Vesicle Pathway NSF; UNC13A 2.44E-05 Reactive Oxygen Species Degradation GPX3; CAT 1.89E-04 Interaction between L1 and Ankyrins SCN11A; NFASC; SCN5A 3.07E-04 Folate Metabolism GPX3; CAT 4.84E-03 L1CAM interactions SCN11A; NFASC; SCN5A 6.23E-03 Selenium Micronutrient Network GPX3; CAT 7.21E-03 Metabolism AMY2A; AMY2B; NUBPL; CAT; AMY1A; AMY1C; AMY1B 1.08E-02 Axon guidance SCN11A; NFASC; SCN5A; TEK 1.66E-02 Phase 0 - Rapid Depolarization SCN11A; SCN5A 2.00E-02 Rac1-Pak1-p38-MMP-2 pathway TNIP1; TEK 2.76E-02 COPI-mediated Anterograde Transport CD59; DCTN4 2.76E-02 Membrane Trafficking AP4S1; CD59; BNIP1; DCTN4 3.64E-02

Downloaded From: https://jamanetwork.com/ on 09/25/2021 eTable 6. Differential Expression of Shared ALS-FTD Risk Genes in Diseased Central Nervous System Tissues

Gene Name Chr PSP p-value FTD p-value ALS p-value MOBP 3 6.43E-02 2.36E-01 2.34E-01 BNIP1 5 1.29E-02 4.79E-03 1.52E-02 C9orf72 9 7.31E-01 N/A N/A MAPT 17 2.16E-01 3.47E-01 1.54E-01 UNC13A 19 3.72E-01 1.00E-03 N/A N/A, not available in dataset.

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eFigure 1. Conditional Manhattan Plots Reveal Novel Risk Loci

A plot of conditional-log10 (FDR) values for ALS (black) given PD (red), AD (orange), CBD (cyan), PSP (green), FTD (purple), TDP43 (blue). SNPs with conditional–log10 FDR > 1.3 (i.e. FDR < 0.05) are shown with large points. A black line around the large points indicates the most significant SNP in each LD block. This SNP was annotated with the closest gene, which is listed above the symbols in each locus.

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eFigure 2. Genetic Enrichment Between ALS, Sporadic FTD, and FTD-TDP43 After Controlling for LD in chr 9 and chr 17 All SNPs in LD with r2 > 0.2 within 1Mb of C9orf72 and MAPT variants (based on 1000 Genomes Project LD structure) were removed from the enrichment analysis. A. Conditional quantile-quantile (Q-Q) plots of empirical -log10 p versus

Downloaded From: https://jamanetwork.com/ on 09/25/2021 nominal -log10 p (corrected for inflation) in ALS below the standard GWAS threshold of p < 5x10-8 as a function of significance of association with and PSP (left panel), sporadic FTD (right panel), and FTD-TDP43 (bottom panel) at p ≤ 0.1, p ≤ 0.01, and p ≤ 0.001, respectively. Blue line indicates all SNPs. B. Fold enrichment plots of enrichment versus nominal -log10 p-values (corrected for inflation) in ALS below the standard GWAS threshold of p < 5x10-8 as a function of significance of association with PSP (left panel), sporadic FTD (right panel), and FTD-TDP43 (bottom panel) at the level of -log10(p) ≥ 0, -log10(p) ≥ 1, -log10(p) ≥ 2 corresponding to p ≤ 1, p ≤ 0.1, p ≤ 0.01, respectively. Blue line indicates all SNPs.

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eFigure 3. Cell-Type Specific Expression of BNIP1 Relative expression of BNIP1 in cell-types isolated from human brain (4).

Downloaded From: https://jamanetwork.com/ on 09/25/2021 eAppendix 1. Methods

IGAP Cohort

International Genomics of Alzheimer's Project (IGAP) is a large two-stage study based upon genome-wide association studies (GWAS) on individuals of European ancestry. In stage 1, IGAP used genotyped and imputed data on 7,055,881 single nucleotide polymorphisms (SNPs) to meta-analyse four previously- published GWAS datasets consisting of 17,008 Alzheimer's disease cases and 37,154 controls (The European Alzheimer's disease Initiative – EADI the Alzheimer Disease Genetics Consortium – ADGC The Cohorts for Heart and Aging Research in Genomic Epidemiology consortium – CHARGE The Genetic and Environmental Risk in AD consortium – GERAD). In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. Finally, a meta- analysis was performed combining results from stages 1 & 2. In this study, we focused on the stage 1 IGAP SNPs.

Genomic Control

The empirical null distribution in GWAS is affected by global variance inflation due to population stratification and cryptic relatedness (1) and deflation due to over-correction of test statistics for polygenic traits by standard genomic control methods (2 ). We applied a control method leveraging only intergenic SNPs, which are likely depleted for true associations (3). SNPs were annotated to genic (5’UTR, exon, intron, 3’UTR) and intergenic regions using information from the 1KGP. Intergenic SNPs were used because their relative depletion of associations suggests that they provide a robust estimate of true null effects and thus seem a better category for genomic control than all SNPs. All p-values were converted to

z-scores and for all phenotypes we estimated the genomic inflation factor λGC for intergenic SNPs. The inflation factor, λGC, was calculated as the median z-score squared divided by the expected median of a chi-square distribution with one degree of freedom and divided all test statistics by λGC.

Downloaded From: https://jamanetwork.com/ on 09/25/2021 eAppendix 2. Acknowledgments

PSP Genetics Consortium Funding: UG3 NS104095 (G. Coppola, D. Dickson, G. Schellenberg, J.Steen), U54NS100693 (L. Petrucelli), and P01-AG-017586 (V.M.-Y.Lee).

IGAP: We thank the International Genomics of Alzheimer's Project (IGAP) for providing summary results data for these analyses. The investigators within IGAP contributed to the design and implementation of IGAP and/or provided data but did not participate in analysis or writing of this report. IGAP was made possible by the generous participation of the control subjects, the patients, and their families. The i–Select chips was funded by the French National Foundation on Alzheimer's disease and related disorders. EADI was supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant, Inserm, Institut Pasteur de Lille, Université de Lille 2 and the Lille University Hospital. GERAD was supported by the Medical Research Council (Grant n° 503480), Alzheimer's Research UK (Grant n° 503176), the Wellcome Trust (Grant n° 082604/2/07/Z) and German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) grant n° 01GI0102, 01GI0711, 01GI0420. CHARGE was partly supported by the NIH/NIA grant R01 AG033193 and the NIA AG081220 and AGES contract N01–AG–12100, the NHLBI grant R01 HL105756, the Icelandic Heart Association, and the Erasmus Medical Center and Erasmus University. ADGC was supported by the NIH/NIA grants: U01 AG032984, U24 AG021886, U01 AG016976, and the Alzheimer's Association grant ADGC–10–196728.

ADGC: The National Institutes of Health, National Institute on Aging (NIH-NIA) supported this work through the following grants: ADGC, U01 AG032984, RC2 AG036528; NACC, U01 AG016976; NCRAD, U24 AG021886; NIA LOAD, U24 AG026395, U24 AG026390; Banner Sun Health Research Institute P30 AG019610; Boston University, P30 AG013846, U01 AG10483, R01 CA129769, R01 MH080295, R01 AG017173, R01 AG025259, R01AG33193; Columbia University, P50 AG008702, R37 AG015473; Duke University, P30 AG028377, AG05128; Emory University, AG025688; Group Health Research Institute, UO1 AG06781, UO1 HG004610; Indiana University, P30 AG10133; Johns Hopkins University, P50 AG005146, R01 AG020688; Massachusetts General Hospital, P50 AG005134; Mayo Clinic, P50 AG016574; Mount Sinai School of Medicine, P50 AG005138, P01 AG002219; New York University, P30 AG08051, MO1RR00096, UL1 RR029893, 5R01AG012101, 5R01AG022374, 5R01AG013616, 1RC2AG036502, 1R01AG035137; Northwestern University, P30 AG013854; Oregon Health & Science University, P30 AG008017, R01 AG026916; Rush University, P30 AG010161, R01 AG019085, R01 AG15819, R01 AG17917, R01 AG30146; TGen, R01 NS059873; University of Alabama at Birmingham, P50 AG016582, UL1RR02777; University of Arizona, R01 AG031581; University of California, Davis, P30 AG010129; University of California, Irvine, P50 AG016573, P50, P50 AG016575, P50 AG016576, P50 AG016577; University of California, Los Angeles, P50 AG016570; University of California, San Diego, P50 AG005131; University of California, San Francisco, P50 AG023501, P01 AG019724; University of Kentucky, P30 AG028383, AG05144; University of Michigan, P50 AG008671; University of Pennsylvania, P30 AG010124; University of Pittsburgh, P50 AG005133, AG030653; University of Southern California, P50 AG005142; University of Texas Southwestern, P30 AG012300; University of Miami, R01 AG027944, AG010491, AG027944, AG021547, AG019757; University of Washington, P50 AG005136; Vanderbilt University, R01 AG019085; and Washington University, P50 AG005681, P01 AG03991. The Kathleen Price Bryan Brain Bank at Duke University Medical Center is funded by NINDS grant # NS39764, NIMH MH60451 and by Glaxo Smith Kline. Genotyping of the TGEN2 cohort was supported by Kronos Science. The TGen series was also funded by NIA grant AG034504 to AJM, The Banner Alzheimer’s Foundation, The Johnnie B. Byrd Sr. Alzheimer’s Institute, the Medical Research Council, and the state of Arizona and also includes samples from the following sites: Newcastle Brain Tissue Resource (funding via the Medical Research Council, local NHS trusts and Newcastle University), MRC London Brain Bank for Neurodegenerative Diseases (funding via the Medical Research Council),South West Dementia Brain Bank (funding via numerous sources including the Higher Education Funding Council for England (HEFCE), Alzheimer’s Research Trust (ART), BRACE as well as North Bristol NHS Trust Research and Innovation Department and DeNDRoN), The Netherlands Brain Bank (funding via numerous sources including Stichting MS Research, Brain Net Europe, Hersenstichting Nederland Breinbrekend Werk, International Parkinson Fonds, Internationale Stiching Alzheimer Onderzoek), Institut de Neuropatologia, Servei Anatomia Patologica, Universitat de Barcelona. ADNI Funding for ADNI is through the Northern California Institute for Research and Education by grants from

Downloaded From: https://jamanetwork.com/ on 09/25/2021 Abbott, AstraZeneca AB, Bayer Schering Pharma AG, Bristol-Myers Squibb, Eisai Global Clinical Development, Elan Corporation, Genentech, GE Healthcare, GlaxoSmithKline, Innogenetics, Johnson and Johnson, Eli Lilly and Co., Medpace, Inc., Merck and Co., Inc., Novartis AG, Pfizer Inc, F. Hoffman-La Roche, Schering-Plough, Synarc, Inc., Alzheimer's Association, Alzheimer's Drug Discovery Foundation, the Dana Foundation, and by the National Institute of Biomedical Imaging and Bioengineering and NIA grants U01 AG024904, RC2 AG036535, K01 AG030514. We thank Drs. D. Stephen Snyder and Marilyn Miller from NIA who are ex-officio ADGC members. Support was also from the Alzheimer’s Association (LAF, IIRG-08-89720; MP-V, IIRG-05-14147) and the US Department of Veterans Affairs Administration, Office of Research and Development, Biomedical Laboratory Research Program. P.S.G.- H. is supported by Wellcome Trust, Howard Hughes Medical Institute, and the Canadian Institute of Health Research. Data for this study were prepared, archived, and distributed by the National Institute on Aging Alzheimer’s Disease Data Storage Site (NIAGADS) at the University of Pennsylvania (U24-AG041689- 01), funded by the National Institute on Aging.

The International FTD-Genomics Consortium (IFGC): Intramural funding from the National Institute of Neurological Disorders and Stroke (NINDS) and National Institute on Aging (NIA), the Wellcome/MRC Centre on Parkinson’s disease, Alzheimer’s Research UK (ARUK, Grant ARUK-PG2012-18) and by the office of the Dean of the School of Medicine, Department of Internal Medicine, at Texas Tech University Health Sciences Center. We thank Mike Hubank and Kerra Pearce at the Genomic core facility at the Institute of Child Health (ICH), University College of London (UCL), for assisting RF in performing Illumina genotyping experiments (FTD-GWAS genotyping). This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, Md. (http://biowulf.nih.gov). North American Brain Expression Consortium (NABEC) - The work performed by the North American Brain Expression Consortium (NABEC) was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, part of the US Department of Health and Human Services; project number ZIA AG000932-04. In addition this work was supported by a Research Grant from the Department of Defense, W81XWH-09-2-0128. UK Brain Expression Consortium (UKBEC) - This work performed by the UK Brain Expression Consortium (UKBEC) was supported by the MRC through the MRC Sudden Death Brain Bank (C.S.), by a Project Grant (G0901254 to J.H. and M.W.) and by a Fellowship award (G0802462 to M.R.). D.T. was supported by the King Faisal Specialist Hospital and Research Centre, Saudi Arabia. Computing facilities used at King's College London were supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. We would like to thank AROS Applied Biotechnology AS company laboratories and Affymetrix for their valuable input. RF’s work is supported by Alzheimer’s Society, UK; JBJK was supported by the National Health and Medical Resarch Council (NHMRC) Australia, Project Grants 510217 and 1005769; CDS was supported by NHMRC Project Grants 630428 and 1005769; PRS was supported by NHMRC Project Grants 510217 and 1005769 and acknowledges that DNA samples were prepared by Genetic Repositories Australia, supported by NHMRC Enabling Grant 401184; GMH was supported by NHMRC Research Fellowship 630434, Project Grant 1029538, Program Grant 1037746; JRH was supported by the Australian Research Council Federation Fellowship, NHMRC Project Grant 1029538, NHMRC Program Grant 1037746; OP was supported by NHMRC Career Development Fellowship 1022684, Project Grant 1003139. IH, AR and MB acknowledge the patients and controls who participated in this project and the Trinitat Port-Carbó and her family who are supporting Fundació ACE research programs. CC was supported by Grant P30-NS069329-01 and acknowledges that the recruitment and clinical characterization of research participants at Washington University were supported by NIH P50 AG05681, P01 AG03991, and P01 AG026276. LB and GB were supported by the Ricerca Corrente, Italian Ministry of Health; RG was supported by Fondazione CARIPLO 2009-2633, Ricerca Corrente, Italian Ministry of Health; GF was supported by Fondazione CARIPLO 2009-2633. ES was supported by the Italian Ministry of Health; CF was supported by Fondazione Cariplo; MS was supported from the Italian Ministry of Health (Ricerca Corrente); MLW was supported by Government funding of clinical research within NHS Sweden (ALF); KN was supported by Thure Carlsson Foundation; CN was supported by Swedish Alzheimer Fund. IRAM and GYRH were supported by CIHR (grant 74580) PARF (grant C06-01). JG was supported by the NINDS intramural research funds for FTD research. CMM was supported by Medical Research Council UK, Brains for Dementia Research, Alzheimer's Society, Alzheimer's Research UK, National Institutes for Health Research, Department of Health, Yvonne Mairy Bequest and acknowledges that tissue made

Downloaded From: https://jamanetwork.com/ on 09/25/2021 available for this study was provided by the Newcastle Brain Tissue Resource, which was funded in part by grants G0400074 and G1100540 from the UK MRC, the Alzheimer’s Research Trust and Alzheimer’s Society through the Brains for Dementia Research Initiative and an NIHR Biomedical Research Centre Grant in Ageing and Health, and NIHR Biomedical Research Unit in Lewy Body Disorders. CMM was supported by the UK Department of Health and Medical Research Council and the Research was supported by the National Institute for Health Research Newcastle Biomedical Research Centre based at Newcastle Hospitals Foundation Trust and Newcastle University and acknowledges that the views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health; JA was supported by MRC, Dunhill Medical Trust, Alzheimer's Research UK; TDG was supported by Wellcome Trust Senior Clinical Fellow; IGM was supported by NIHR Biomedical Research Centre and Unit on Ageing Grants and acknowledges the National Institute for Health Research Newcastle Biomedical Research Centre based at Newcastle Hospitals Foundation Trust and Newcastle University. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health; AJT was supported by Medical Research Council, Alzheimer's Society, Alzheimer's Research UK, National Institutes for Health Research. EJ was supported by NIHR, Newcastle Biomedical Research Centre. PP, CR, SOC and EA were supported partially by FIMA (Foundation for Applied Medical Research); PP acknowledges Manuel Seijo-Martínez (Department of Neurology, Hospital do Salnés, Pontevedra, Spain), Ramon Rene, Jordi Gascon and Jaume Campdelacreu (Department of Neurology, Hospital de Bellvitge, Barcelona, Spain) for providing FTD DNA samples. RP, JDS, PA and AK were supported by German Federal Ministry of Education and Research (BMBF; grant number FKZ 01GI1007A – German FTLD consortium). IR was supported by Ministero dell'Istruzione, dell'Università e della Ricerca (MIUR) of Italy. PStGH was supported by the Canadian Institutes of Health Research, Wellcome Trust, Ontario Research Fund. FT was supported by the Italian Ministry of Health (ricerca corrente) and MIUR grant RBAP11FRE9; GR and GG were supported by the Italian Ministry of Health (ricerca corrente). JBR was supported by Camrbidge NIHR Biomedical Research Centre and Wellcome Trust (088324). JU, JC, SM were supported by the MRC Prion Unit core funding and acknowledge MRC UK, UCLH Biomedical Research Centre, Queen Square Dementia BRU; SM acknowledges the work of John Beck, Tracy Campbell, Gary Adamson, Ron Druyeh, Jessica Lowe, Mark Poulter. AD acknowledges the work of Benedikt Bader and of Manuela Neumann, Sigrun Roeber, Thomas Arzberger and Hans Kretzschmar†; VMVD and JQT were supported by Grants AG032953, AG017586 and AG010124; MG was supported by Grants AG032953, AG017586, AG010124 and NS044266; VMVD acknowledges EunRan Suh, PhD for assistance with sample handling and Elisabeth McCarty-Wood for help in selection of cases; JQT acknowledges Terry Schuck, John Robinson and Kevin Raible for assistance with neuropathological evaluation of cases. CVB and the Antwerp site were in part funded by the MetLife Foundation for Medical Research Award (to CVB), the Belgian Science Policy Office (BELSPO) Interuniversity Attraction Poles program; the Alzheimer Research Foundation (SAO-FRA); the Medical Foundation Queen Elisabeth (GSKE); the Flemish Government initiated Methusalem Excellence Program (to CVB); the Research Foundation Flanders (FWO) and the University of Antwerp Research Fund.. CVB, MC and JvdZ acknowledge the neurologists S Engelborghs, PP De Deyn, A Sieben, R Vandenberghe and the neuropathologist JJ Martin for the clinical and pathological diagnoses. CVB, MC and JvdZ further thank the personnel of the Genetic Service Facility of the VIB Department of Molecular Genetics (http://www.vibgeneticservicefacility.be) and the Antwerp Biobank of the Institute Born-Bunge for their expert support. IL and AB were supported by the program “Investissements d’avenir” ANR-10-IAIHU-06 and acknowledges the contribution of The French research network on FTLD/FTLD-ALS for the contribution in samples collection. BN is founded by Fondazione Cassa di Risparmio di Pistoia e Pescia (grant 2014.0365), SS is founded by the Cassa di Risparmio di Firenze (grant 2014.0310) and a grant from Ministry of Health n° RF-2010-2319722. JEN was supported by the Novo Nordisk Foundation, Denmark. MR was supported by the German National Genome Network (NGFN); German Ministry for Education and Research Grant Number 01GS0465. JDR, MNR, NCF and JDW were supported by an MRC programme grant, the NIHR Queen Square Dementia Biomedical Research Unit (BRU) and the Leonard Wolfson Experimental Neurology Centre. MGS was supported by MRC grant n G0301152, Cambridge Biomedical Research Centre and acknowledges Mrs K Westmore for extracting DNA. HM was supported by the Motor Neuron Disease Association (Grant 6057). RR was supported by P50 AG016574, R01 NS080882, R01 NS065782, P50 NS72187 and the Consortium for Frontotemporal Dementia; DWD was supported by P50NS072187, P50AG016574, State of Florida Alzheimer Disease Initiative, & CurePSP, Inc.; NRGR, JEP, RCP, DK, BFB were supported by P50 AG016574; KAJ was supported by R01

Downloaded From: https://jamanetwork.com/ on 09/25/2021 AG037491; WWS was supported by NIH AG023501, AG019724, Consortium for Frontotemporal Dementia Research; BLM was supported by P50AG023501, P01AG019724, Consortium for FTD Research; HR was supported by AG032306. JCvS was supported by Stichting Dioraphte Foundation (11 02 03 00), Nuts Ohra Foundation (0801-69), Hersenstichting Nederland (BG 2010-02) and Alzheimer Nederland. CG and HHC acknowledge families, patients, clinicians including Dr Inger Nennesmo and Dr Vesna Jelic, Professor Laura Fratiglioni for control samples and Jenny Björkström, Håkan Thonberg, Charlotte Forsell, Anna-Karin Lindström and Lena Lilius for sample handling. CG was supported by Swedish Brain Power (SBP), the Strategic Research Programme in Neuroscience at Karolinska Institutet (StratNeuro), the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet, Swedish Alzheimer Foundation, Swedish Research Council, Karolinska Institutet PhD-student funding, King Gustaf V and Queen Victoria’s Free Mason Foundation. FP, AR, VD and FL acknowledge Labex DISTALZ. RF acknowledges the help and support of Mrs. June Howard at the Texas Tech University Health Sciences Center Office of Sponsored Programs for tremendous help in managing Material Transfer Agreement at TTUHSC.

The International Parkinson’s Disease Genomics Consortium (IPDGC): We would like to thank all of the subjects who donated their time and biological samples to be a part of this study. This work was supported in part by the Intramural Research Programs of the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute on Aging (NIA), and the National Institute of Environmental Health Sciences both part of the National Institutes of Health, Department of Health and Human Services; project numbers Z01-AG000949-02 and Z01-ES101986. In addition this work was supported by the Department of Defense (award W81XWH-09-2-0128), and The Michael J Fox Foundation for Parkinson’s Research. This work was supported by National Institutes of Health grants R01NS037167, R01CA141668, P50NS071674, American Parkinson Disease Association (APDA); Barnes Jewish Hospital Foundation; Greater St Louis Chapter of the APDA; Hersenstichting Nederland; Neuroscience Campus Amsterdam; and the section of medical genomics, the Prinses Beatrix Fonds. The KORA (Cooperative Research in the Region of Augsburg) research platform was started and financed by the Forschungszentrum für Umwelt und Gesundheit, which is funded by the German Federal Ministry of Education, Science, Research, and Technology and by the State of Bavaria. This study was also funded by the German National Genome Network (NGFNplus number 01GS08134, German Ministry for Education and Research); by the German Federal Ministry of Education and Research (NGFN 01GR0468, PopGen); and 01EW0908 in the frame of ERA-NET NEURON and Helmholtz Alliance Mental Health in an Ageing Society (HA-215), which was funded by the Initiative and Networking Fund of the Helmholtz Association. The French GWAS work was supported by the French National Agency of Research (ANR-08-MNP-012). This study was also funded by France-Parkinson Association, the French program “Investissements d’avenir” funding (ANR-10- IAIHU-06) and a grant from Assistance Publique-Hôpitaux de Paris (PHRC, AOR-08010) for the French clinical data. This study was also sponsored by the Landspitali University Hospital Research Fund (grant to SSv); Icelandic Research Council (grant to SSv); and European Community Framework Programme 7, People Programme, and IAPP on novel genetic and phenotypic markers of Parkinson’s disease and Essential Tremor (MarkMD), contract number PIAP-GA-2008-230596 MarkMD (to HP and JHu). This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, Md. (http://biowulf.nih.gov), and DNA panels, samples, and clinical data from the National Institute of Neurological Disorders and Stroke Human Genetics Resource Center DNA and Cell Line Repository. People who contributed samples are acknowledged in descriptions of every panel on the repository website. We thank the French Parkinson’s Disease Genetics Study Group and the Drug Interaction with genes (DIGPD) study group: Y Agid, M Anheim, A-M Bonnet, M Borg, A Brice, E Broussolle, J-C Corvol, P Damier, A Destée, A Dürr, F Durif, A Elbaz, D Grabil, S Klebe, P. Krack, E Lohmann, L. Lacomblez, M Martinez, V Mesnage, P Pollak, O Rascol, F Tison, C Tranchant, M Vérin, F Viallet, and M Vidailhet. We also thank the members of the French 3C Consortium: A Alpérovitch, C Berr, C Tzourio, and P Amouyel for allowing us to use part of the 3C cohort, and D Zelenika for support in generating the genome-wide molecular data. We thank P Tienari (Molecular Neurology Programme, Biomedicum, University of Helsinki), T Peuralinna (Department of Neurology, Helsinki University Central Hospital), L Myllykangas (Folkhalsan Institute of Genetics and Department of Pathology, University of Helsinki), and R Sulkava (Department of Public Health and General Practice Division of Geriatrics, University of Eastern Finland) for the Finnish controls (Vantaa85+ GWAS data). We used

Downloaded From: https://jamanetwork.com/ on 09/25/2021 genome-wide association data generated by the Wellcome Trust Case-Control Consortium 2 (WTCCC2) from UK patients with Parkinson’s disease and UK control individuals from the 1958 Birth Cohort and National Blood Service. Genotyping of UK replication cases on ImmunoChip was part of the WTCCC2 project, which was funded by the Wellcome Trust (083948/Z/07/Z). UK population control data was made available through WTCCC1. This study was supported by the Medical Research Council and Wellcome Trust disease centre (grant WT089698/Z/09/Z to NW, JHa, and ASc). As with previous IPDGC efforts, this study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113, 085475 and 090355. This study was also supported by Parkinson’s UK (grants 8047 and J-0804) and the Medical Research Council (G0700943). We thank Jeffrey Barrett for assistance with the design of the ImmunoChip. DNA extraction work that was done in the UK was undertaken at University College London Hospitals, University College London, who received a proportion of funding from the Department of Health’s National Institute for Health Research Biomedical Research Centres funding. This study was supported in part by the Wellcome Trust/Medical Research Council Joint Call in Neurodegeneration award (WT089698) to the Parkinson’s Disease Consortium (UKPDC), whose members are from the UCL Institute of Neurology, University of Sheffield, and the Medical Research Council Protein Phosphorylation Unit at the University of Dundee.

Mayo RNAseq: Study data were provided by the following sources: The Mayo Clinic Alzheimers Disease Genetic Studies, led by Dr. Nilufer Taner and Dr. Steven G. Younkin, Mayo Clinic, Jacksonville, FL using samples from the Mayo Clinic Study of Aging, the Mayo Clinic Alzheimers Disease Research Center, and the Mayo Clinic Brain Bank. Data collection was supported through funding by NIA grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949, NINDS grant R01 NS080820, CurePSP Foundation, and support from Mayo Foundation. Study data includes samples collected through the Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinsons Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimers Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimers Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson's Disease Consortium) and the Michael J. Fox Foundation for Parkinsons Research.

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