Supplementary Information Genome-wide association analyses of risk tolerance and risky behaviors in over one million individuals identify hundreds of loci and shared genetic influences Correspondence to: [email protected] or [email protected] TABLE OF CONTENTS 1 STUDY OVERVIEW ............................................................................................................. 4 1.1 STUDY MOTIVATION ........................................................................................................... 4 1.2 PHENOTYPE DEFINITIONS .................................................................................................... 4 2 GWAS, QUALITY CONTROL AND META-ANALYSIS ............................................. 10 2.1 OVERVIEW OF PRIMARY GWAS ....................................................................................... 10 2.2 GENOTYPING AND IMPUTATION ........................................................................................ 11 2.3 ASSOCIATION ANALYSES .................................................................................................. 11 2.4 MAIN REFERENCE PANEL .................................................................................................. 12 2.5 QUALITY CONTROL OF ALLELE-FREQUENCY DIFFERENCES BETWEEN THE UK BIOBANK GENOTYPING ARRAYS ................................................................................................................. 14 2.6 DESCRIPTION OF MAJOR STEPS IN QUALITY-CONTROL (QC) ANALYSES ............................ 15 2.7 META-ANALYSIS AND ADJUSTMENT OF THE STANDARD ERRORS ...................................... 18 2.8 INDEPENDENCE OF SIGNIFICANT LOCI AND DEFINITION OF LOCUS ..................................... 19 2.9 CHECK FOR LONG-RANGE LD REGIONS, CANDIDATE INVERSIONS, AND 1000 GENOMES STRUCTURAL VARIANTS .............................................................................................................. 20 2.10 INVESTIGATION OF THE NOVELTY OF OUR GWAS ASSOCIATIONS .................................... 21 2.11 GWAS CATALOG LOOKUP ................................................................................................ 22 2.12 CROSS-LOOKUP OF GWAS RESULTS ................................................................................ 23 2.13 GENE ANNOTATION .......................................................................................................... 23 3 GWAS RESULTS ................................................................................................................ 24 3.1 SUMMARY OF THE GWAS RESULTS ................................................................................. 24 3.2 SUMMARY OF GENETIC OVERLAP ACROSS OUR MAIN GWAS ........................................... 25 3.3 RESULTS OF THE DISCOVERY GWAS OF GENERAL RISK TOLERANCE ................................ 30 3.4 RESULTS OF THE SUPPLEMENTARY GWAS ....................................................................... 37 4 TESTING FOR POPULATION STRATIFICATION ..................................................... 44 4.1 LD SCORE INTERCEPT TEST .............................................................................................. 44 4.2 GWAS/WF GWAS SIGN TEST FOR THE GENERAL-RISK-TOLERANCE GWAS .................. 45 4.3 DISCUSSION ...................................................................................................................... 50 5 OUT-OF-SAMPLE REPLICATION OF THE LEAD SNPS FROM OUR DISCOVERY GWAS OF GENERAL RISK TOLERANCE ................................................. 51 6 ESTIMATION OF GENOME-WIDE SNP HERITABILITY ........................................ 54 6.1 METHODS TO ESTIMATE GENOME-WIDE SNP HERITABILITY ............................................. 54 6.2 RESULTS OF GENOME-WIDE SNP HERITABILITY ESTIMATION ........................................... 55 7 GENETIC CORRELATIONS ............................................................................................ 57 7.1 METHODOLOGY ................................................................................................................ 57 7.2 PRE-SELECTED PHENOTYPES ............................................................................................. 58 7.3 RESULTS: GENETIC CORRELATION BETWEEN GENERAL RISK TOLERANCE AND PRE- SELECTED PHENOTYPES .............................................................................................................. 59 2 7.4 OTHER RESULTS ............................................................................................................... 62 7.5 COMPARISON OF THE GENETIC AND PHENOTYPIC CORRELATIONS ..................................... 62 7.6 APPENDIX: GWAS OF OTHER RISKY BEHAVIORS AND OF SOCIOECONOMIC PHENOTYPES USING THE FIRST RELEASE OF UKB DATA ................................................................................... 64 8 PROXY-PHENOTYPE ANALYSES ................................................................................. 66 8.1 INTRODUCTION ................................................................................................................. 66 8.2 METHODOLOGY ................................................................................................................ 66 8.3 RESULTS FROM PROXY-PHENOTYPE ENRICHMENT ANALYSES ........................................... 68 9 MULTI-TRAIT ANALYSIS OF GWAS (MTAG) ........................................................... 72 9.1 INTRODUCTION ................................................................................................................. 72 9.2 METHODS ......................................................................................................................... 72 9.3 RESULTS ........................................................................................................................... 73 10 PREDICTIVE POWER OF GENERAL-RISK-TOLERANCE POLYGENIC SCORE 75 10.1 PHENOTYPE DEFINITION ................................................................................................... 76 10.2 METHODS ......................................................................................................................... 86 10.3 RESULTS ........................................................................................................................... 90 10.4 EXPECTED PREDICTIVE POWER OF GENERAL-RISK-TOLERANCE POLYGENIC SCORE .......... 94 10.5 APPENDIX: DEFINITION OF THE INCOME RISK GAMBLE VARIABLE IN THE HRS COHORT AND MERGER OF THE STR1 AND STR2 COHORTS ............................................................................... 96 11 TESTING HYPOTHESES ABOUT SPECIFIC GENES AND GENE SETS ................ 99 11.1 LITERATURE REVIEW ........................................................................................................ 99 11.2 GENE ANALYSIS AND COMPETITIVE GENE-SET ANALYSES WITH MAGMA ..................... 101 11.3 DISCUSSION .................................................................................................................... 106 12 BIOLOGICAL ANNOTATION ....................................................................................... 107 12.1 FUNCTIONAL PARTITIONING OF HERITABILITY WITH STRATIFIED LD SCORE REGRESSION 108 12.2 IDENTIFYING GENES ASSOCIATED WITH GENERAL RISK TOLERANCE WITH MAGMA ..... 112 12.3 IDENTIFYING GENES ASSOCIATED WITH GENERAL RISK TOLERANCE WITH SMR ............. 115 12.4 PRIORITIZATION OF TISSUES, GENE SETS, AND GENES USING DEPICT ............................ 119 12.5 COMPETITIVE GENE-SET ANALYSIS WITH MAGMA: TESTING GENE SETS RELATED TO GABA AND GLUTAMATE NEUROTRANSMITTERS ...................................................................... 122 12.6 LOOKUP OF PROTEIN-ALTERING VARIANTS AND CIS-EQTLS ........................................... 123 12.7 SUMMARY OF MAIN FINDINGS FROM THE BIOLOGICAL ANNOTATION ANALYSES ............. 126 13 ADDITIONAL INFORMATION ..................................................................................... 131 13.1 AUTHOR CONTRIBUTIONS ............................................................................................... 131 13.2 COHORT-LEVEL CONTRIBUTIONS .................................................................................... 132 13.3 ADDITIONAL ACKNOWLEDGMENTS ................................................................................. 134 14 REFERENCES ................................................................................................................... 138 3 1 Study overview 1.1 Study motivation Risk tolerance, or the willingness to take risks to obtain rewards, is a fundamental parameter in economics, finance, and behavioral decision theory. Different measures of risk preferences have previously been linked to real-world behaviors such as portfolio allocation and occupational choice, as well as health behaviors such as smoking, exercising, and alcohol and drug use1–5. Further, recent work has demonstrated the existence of a reliable general factor of risk preference that is generalizable both to specific and real-world risky behaviors6. Elucidating the determinants of individual differences in general risk tolerance is an active field of research3,4. General risk tolerance has been found to be moderately heritable in twin studies (ℎ"~30%), although heritability estimates in the literature vary, ranging from 20% to 60%2,7–9; an earlier study based on molecular genetic data had confirmed the heritability of the trait10. Some previous studies have attempted to identify specific genetic