Social regulation of gene expression

Steve W. Cole, Ph.D. UCLA School of Medicine Division of Hematology-Oncology IL6 DNA

Gene IL6 DNA

Gene RNA

IL6 DNA

Gene Health

RNA

IL6 DNA

Gene Early life social conditions S. Suomi

521 717

Mother reared

Peer reared Health

RNA

IL6 DNA

Gene Health

RNA

IL6 DNA

Gene Social Environment

Health

RNA

IL6 DNA

Gene Social Environment

Health

RNA

IL6 DNA

Gene Social Environment

Health

RNA

IL6 DNA

Gene Social Environment

Health

RNA

IL6 DNA

Gene Social signal transduction

Social processes

Genome Social signal transduction

Social processes

CNS function

Genome Social signal transduction

Social processes

CNS function

Peripheral neurobiology

Genome Social signal transduction

Social processes

CNS function

Peripheral neurobiology

Cell signal transduction

Genome Social signal transduction

Social processes

CNS function

Peripheral neurobiology

Cell signal transduction

Transcription factors

Genome Social signal transduction

Social processes

CNS function

Peripheral neurobiology

Cell signal transduction

Transcription factors

Genome Social signal transduction

Social processes Simple questions CNS function

Peripheral neurobiology

Cell signal transduction

Transcription factors

Genome Social signal transduction

Social processes Simple questions CNS 1. Which gene modules are function sensitive to social processes?

Peripheral neurobiology

Cell signal transduction

Transcription factors

Genome Social signal transduction

Social processes Simple questions CNS 1. Which gene modules are function sensitive to social processes?

2. Which transcription control Peripheral pathways mediate those effects? neurobiology

Cell signal transduction

Transcription factors

Genome Social signal transduction

Social processes Simple questions CNS 1. Which gene modules are function sensitive to social processes?

2. Which transcription control Peripheral pathways mediate those effects? neurobiology 3. Which genetic polymorphisms modulate social influences? Cell signal transduction

Transcription factors

Genome Social signal transduction

Social processes Simple questions CNS 1. Which gene modules are function sensitive to social processes?

2. Which transcription control Peripheral pathways mediate those effects? neurobiology 3. Which genetic polymorphisms modulate social influences? Cell signal transduction

Transcription factors

Genome ? Early life social conditions S. Suomi

521 717

Mother reared

Peer reared Early life social conditions S. Suomi

Inflammation Cell growth/differentiation Transcription control 521 717

Mother reared

Peer reared Early life social conditions S. Suomi

Inflammation Cell growth/differentiation Transcription control 521 717

Mother reared

Peer reared

Immunoglobulin production Type I interferon antiviral response Low SES Early life low SES Social threat Social loss / anticipated bereav ement Social instability Adolescent role incongruity Loneliness Introversion Acute stress Chronic stress Depression Sleep loss Social signal transduction

Isolation Low SES Social threat Bereavement

CNS function

Peripheral neurobiology

Cell signal transduction

Transcription factors

Genome CTRA – conserved transcriptional response to adversity

Inflammation Cell growth/differentiation Transcription control 521 717

Mother reared

Peer reared

Immunoglobulin G1 production Type I interferon antiviral response CTRA – conserved transcriptional response to adversity

Inflammation Cell growth/differentiation Transcription control 521 717

Mother reared

Peer reared

Immunoglobulin G1 production Type I interferon antiviral response CTRA – conserved transcriptional response to adversity

Inflammation Cell growth/differentiation Transcription control 521 717

Mother reared

Peer reared

Immunoglobulin G1 production Type I interferon antiviral response CTRA – conserved transcriptional response to adversity

Inflammation Cell growth/differentiation Transcription control 521 717

Mother reared

Peer reared

Immunoglobulin G1 production Type I interferon antiviral response hthate = btibacteria hthate = btibacteria loneliness = predation hthate = btibacteria loneliness = predation = bacteria hthate = btibacteria loneliness = predation = bacteria

love = viruses Social signal transduction

Social processes Simple questions CNS 1. Which gene modules are function sensitive to social processes?

2. Which transcription control Peripheral pathways mediate those effects? neurobiology 3. Which genetic polymorphisms modulate social influences? Cell signal transduction

Transcription factors

Genome Social signal transduction

Social processes Simple questions CNS 1. Which gene modules are function sensitive to social processes?

2. Which transcription control Peripheral pathways mediate those effects? neurobiology 3. Which genetic polymorphisms modulate social influences? Cell signal transduction ?

Transcription factors

Genome Social Environment

Health

RNA

IL6 DNA

Gene Social Environment

Health

RNA

IL6 DNA

Gene Social Environment

Health

RNA

IL6 DNA

Gene Social Environment

Health

RNA

IL6 DNA

Gene Social Environment

Health

RNA

IL6 DNA

Gene Early life social conditions

521 717

Mother reared

Peer reared Early life social conditions

CREB / ATF EGR1, EGR3, EGR4/NGFIC NRF2 GATA 521 717

Mother reared

Peer reared

MAF, MZF1 ISRE, STAT1 Social Environment

Health

RNA

IL6 DNA

Gene Social Environment

Health

RNA

IL6 DNA

Gene Immune cell target of social adversity

Transcript origin cell diagnostic Z-score p-value

Monocytes .0001

Dendritic cells .1973

NK cells .2733

CD4+ T cells .9989

CD8+ T cells .9999

B cells .2609

-1.0 -0.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0

Suomi results unpublished; method: Cole et al (2011) Proc Nat Acad Sci USA Social signal transduction

Social processes Simple questions CNS 1. Which gene modules are function sensitive to social processes?

2. Which transcription control Peripheral pathways mediate those effects? neurobiology 3. Which genetic polymorphisms modulate social influences? Cell signal transduction

Transcription factors

Genome Social signal transduction

Social processes Simple questions CNS 1. Which gene modules are function sensitive to social processes?

2. Which transcription control Peripheral pathways mediate those effects? neurobiology 3. Which genetic polymorphisms modulate social influences? Cell signal transduction

Transcription factors

Genome ? System properties

Social processes

CNS function

Peripheral neurobiology

Cell signal transduction

Transcription factors

Genome System properties

Social processes

CNS function 1. Subjectivity

Peripheral neurobiology

Cell signal transduction

Transcription factors

Genome System properties

Social processes

CNS function 1. Subjectivity

Peripheral neurobiology

Cell signal transduction

Transcription factors

Genome 2. Basal remodeling System properties

Social processes

CNS function 1. Subjectivity

Peripheral neurobiology

Cell signal transduction

Transcription factors

Genome 2. Basal remodeling System properties

Social processes

CNS function 1. Subjectivity

Peripheral neurobiology

Cell signal transduction

Transcription factors

Genome 2. Basal remodeling System properties

Social processes

CNS function 1. Subjectivity

Peripheral neurobiology

Cell signal transduction

Transcription factors 3. Recursive persistence

Genome 2. Basal remodeling

SNS NGF LN Recursive developmental remodeling

Body1

Cole (2009) Current Directions in Psychological Science Recursive developmental remodeling

Environment1 Body1

Cole (2009) Current Directions in Psychological Science Recursive developmental remodeling

Behavior1 Environment1 Body1

Cole (2009) Current Directions in Psychological Science Recursive developmental remodeling

Behavior1 Environment1 Body1 RNA1

Cole (2009) Current Directions in Psychological Science Recursive developmental remodeling

Behavior1 Environment1 Body1 RNA1

Body2

Cole (2009) Current Directions in Psychological Science Recursive developmental remodeling

Behavior1 Environment1 Body1 RNA1

Environment2 Body2

Cole (2009) Current Directions in Psychological Science Recursive developmental remodeling

Behavior1 Environment1 Body1 RNA1

Behavior2 Environment2 Body2 RNA2

Cole (2009) Current Directions in Psychological Science Recursive developmental remodeling

Behavior1 Environment1 Body1 RNA1

Behavior2 Environment2 Body2 RNA2

Behavior3 Environment3 Body3 RNA3

Cole (2009) Current Directions in Psychological Science Recursive developmental remodeling

Behavior1 Time 1 Environment1 Body1 RNA1

Behavior2 Time 2 Environment2 Body2 RNA2

Behavior3 Time 3 Environment3 Body3 RNA3

RNA = intra-organismic adaptation

Cole (2009) Current Directions in Psychological Science System properties

Social processes

CNS function 1. Subjectivity

Peripheral neurobiology

Cell signal transduction

Transcription factors 3. Recursive persistence

Genome 2. Basal remodeling

SNS NGF LN System properties 4. Environmental recursion

Social processes

CNS function 1. Subjectivity

Peripheral neurobiology

Cell signal transduction

Transcription factors 3. Recursive persistence

Genome 2. Basal remodeling

SNS NGF LN System properties 4. Environmental recursion

Social processes Behavior

CNS function 1. Subjectivity

Peripheral neurobiology

Cell signal transduction

Transcription factors 3. Recursive persistence

Genome 2. Basal remodeling

SNS NGF LN System properties 4. Environmental recursion

Social processes Behavior

CNS function 1. Subjectivity

Peripheral neurobiology

Cell signal transduction

Transcription factors 3. Recursive persistence

Genome 2. Basal remodeling

SNS NGF LN Recursive developmental remodeling

Behavior1 Time 1 Environment1 Body1 RNA1

Behavior2 Time 2 Environment2 Body2 RNA2

Behavior3 Time 3 Environment3 Body3 RNA3

RNA = intra-organismic adaptation

Cole (2009) Current Directions in Psychological Science Recursive developmental remodeling

Behavior1 Time 1 Environment1 Body1 RNA1

Behavior2 Time 2 Environment2 Body2 RNA2

Behavior3 Time 3 Environment3 Body3 RNA3

RNA = intra-organismic adaptation

Cole (2009) Current Directions in Psychological Science Recursive developmental remodeling

Behavior1 Time 1 Environment1 Body1 RNA1

Behavior2 Time 2 Environment2 Body2 RNA2

Behavior3 Time 3 Environment3 Body3 RNA3

RNA = intra-organismic adaptation

Cole (2009) Current Directions in Psychological Science Your experiences today will influence the molecular composition of your body for the next 2-3 months Your experiences today will influence the molecular composition of your body for the next 2-3 months

… or perhaps the rest of your life. Your experiences today will influence the molecular composition of your body for the next 2-3 months

… or perhaps the rest of your life.

Plan your day accordingly. Collaborators Steve Suomi, James Heckman John Cacioppo, Louise Hawkley, Bob Rose Greg Miller, Edith Chen Susan Lutgendorf, Anil Sood John Sheridan JhJohn Cap itiitanio, EiErica Sloan Mike Irwin, Patti Ganz, Julie Bower Margaret Kemeny, Jerry Zack Teresa Seeman, Andrew Fuligni

Support NCI CA116778, CA110793, CA109298 NIAID AI33259, AI36554, AI49135, AI52737 NIA AG107265, AG033590, AG34679 NIMH MH00820, MH1575 0 NCRR RR020645 UC Universitywide AIDS Research Program UCLA AIDS Institute MacArthur Foundation James Pendleton Charitable Trust Santa Fe Institute for Complex Systems Norman Cousins Center

Social signal transduction

Social processes Simple questions CNS 1. Which gene modules are function sensitive to social processes?

2. Which transcription control Peripheral pathways mediate those effects? neurobiology 3. Which genetic polymorphisms modulate social influences? Cell signal transduction

Transcription factors

Genome ? Social Environment

Health

RNA

IL6 DNA

Gene Social Environment

Health

RNA

… [G/C] … IL6 DNA

Gene Social Environment

Health

RNA

… [G/C] … IL6 DNA

Gene Social Environment

… [G/C] … IL6 DNA

Gene Gene x Environment Interaction

In silico In vitro

IL6 promoter: WT -174C

Difference: p < .0001

10 V$GATA1_01 = .943

TCT TGCGATGCTA AAG 8

IL6 ity vv C 6 V$GATA1_01 = .619 ld-change)

riptional acti 4 oo cc (f

Trans 2

0 Norepinephrine (M): 0 10 - 0 10

Cole et al. (2010) Proceedings of the National Academy of Sciences Gene x Environment Interaction

IL6 -174 GG IL6 -174 CC/GC 0 0 .. p = .008 .. p = .439 0.8 1 0.8 1 66 66 Survival 0.4 0. 0.4 0.

Non-depressed Non-depressed Depressed Depressed 0.0 0.2 0.0 0.2

70 80 90 70 80 90

Age Age

Cole et al. (2010) Proceedings of the National Academy of Sciences Social Environment

Health

RNA

…GATG… IL6 DNA Advers ity (depressi on) Social Environment

Health

RNA

…GATG… IL6 DNA Advers ity (depressi on) Social Environment SNS / NE

Health

RNA

…GATG… IL6 DNA Advers ity (depressi on) Social Environment SNS / NE

Health -AR

RNA

…GATG… IL6 DNA Advers ity (depressi on) Social Environment SNS / NE

Health -AR

GATA1 RNA

…GATG… IL6 DNA Advers ity (depressi on) Social Environment SNS / NE

Health -AR

GATA1 RNA

…GATG… IL6IL6 DNA Advers ity (depressi on) Social Environment SNS / NE Inflammation Health -AR

GATA1 RNA

…GATG… IL6IL6 DNA Advers ity (depressi on) Social Environment Mortality risk SNS / NE Inflammation Health -AR

GATA1 RNA

…GATG… IL6IL6 DNA Advers ity (depressi on) Social Environment Mortality risk SNS / NE Inflammation Health -AR

GATA1 RNA

…GATG… IL6IL6 DNA rs1800795 Advers ity (depressi on) Social Environment Mortality risk SNS / NE Inflammation Health -AR

GATA1 RNA

…GATG… IL6IL6 DNA rs1800795 Advers ity (depressi on) Social Environment SNS / NE

-AR GATA1

…GATG… IL6IL6 DNA rs1800795 The experienced self • stable • independent The experienced self • stable • independent

The molecular self • fluid • permeable RHCE 292 IBSP 319 LOC442279 -858 TNFRSF12A -968 RHCE -292 LOC150221 -939 MGC48628 -101 SPAG11 -622 FANK1 3 CLECSF12 -885 PSMC4 -215 LOC401289 -82 DNAJA3 -24 RHCE -292 LOC91219 -352 NDST3 -902 SPAG11 -622 TAF3 -544 CLECSF12 -885 PSMC4 -215 LOC285766 -472 ALG1 -464 RHCE -292 LOC150236 -666 LOC401149 -733 SPAG11 -971 LOC441547 9 CLECSF12 -885 EGLN2 -452 SERPINB6 -657 ALG1 -464 LOC440576 -934 GSTT1 -141 LOC441038 -837 DEFB104 -132 LOC220998 -941 CLECSF12 -885 LOC388549 -412 OFCC1 -367 FLJ12363 -773 SOC -39 SEC14L4 -746 FLJ35630 -291 LOC389633 -370 TPRT -277 CLECSF12 -885 SYNGR4 -825 LOC441129 -714 LOC92017 -711 SOC -49 SSTR3 -705 CYP4V2 -117 ASAH1 -702 C10orf68 -817 CLECSF12 -885 RPL13A -816 SMA3 -762 TMC7 -412 SOC -26 FLJ22582 -372 LOC401164 -978 ASAH1 -882 C10orf9 -269 CLECSF12 -885 LOC402665 -925 LOC222699 -719 MGC16824 -271 UNQ6122 -877 DIA1 -749 LOC391727 -934 FLJ22494 -242 ZNF33A -477 CLECSF12 -885 FLJ46385 -176 LOC441138 -870 RBBP6 -795 LAPTM5 -728 ATP5L2 -328 LOC399917 -840 FLJ22494 -781 ZNF33A -477 CLECSF12 -885 LOC91661 -13 OR12D3 -872 RBBP6 -795 PHC2 -168 A4GALT -825 ZAR1 -106 SNAI2 -728 LOC399744 -202 KLRK1 -349 LAIR2 -705 LOC346171 -389 RBBP6 -795 PHC2 -16 SULT4A1 -729 LOC401132 -18 CPA6 -613 LOC399744 -202 PRB1 -589 LAIR2 -705 HCG4P6 -80 ITGAX -504 ITGB3BP -311 SULT4A1 -729 PF4 -819 FSBP -393 PPYR1 -81 PRB1 -589 KIR2DL1 -763 HCG4P6 -501 ERAF -510 FLJ20331 -994 C2orf15 -882 EIF4E -716 MFTC -905 PPYR1 -81 PRB1 -589 KIR3DL2 3 PSORS1C2 -78 LOC388248 -649 ZNF265 -663 LOC129521 -477 ADH7 -557 MRPL13 -525 LOC439946 -71 ADAMTS20 -965 ZNF583 -867 1205PSORS1C2 GRE-modifying -78 AKR1C2 SNPs -641 FLJ38101 -981 ZNF265 -663 LOC440892 -918 TACR3 -957 LOC442399 -126 ADAMTS20 -965 ZNF71 -861 HLA-C -512 CES4 -221 FUBP1FUBP1 -777788 IL1RL1 -332 AGXT2L1 -631 TOP1MT -477 AKR1C2 -641 SLC38A2 -638 MGC4728 -490 HLA-B -594 MT1H -280 LOC388650 -392 MRPS9 -970 PLA2G12A -795 LOC286126 -887 LOC441560 -504 K-ALPHA-1 -27 ZNF211 -76 HLA-DRB1 -469 GAN -839 LOC388654 -957 LOC442037 -839 PITX2 -411 LOC340393 -922 LOC439975 -618 KIAA1602 -262 ZNF211 -76 HLA-DRB1 -821 PLCG2 -534 PDE4DIP -175 IL1F7 -978 PITX2 -411 DOCK8 -109 NEUROG3 6 RACGAP1 -620 LOC401895 -957 HLA-DQB2 0 CDH13 -906 COAS2 -435 IL1F7 -978 LOC401155 -72 LOC441386 -327 AMID -452 K6IRS3 -708 APBA3 -13 HLA-DQB2 -333 HSBP1 -425 LOC199882 -474 IL1F7 -978 CDHJ -652 C9orf93 -708 PPP3CB -854 KRT4 -83 FUT5 -174 HLA-DQB2 0 MLYCD -917 LOC440689 -692 IL1F7 -978 FGA -110 SH3GL2 -702 LOC439983 -240 NPFF -777 TNFSF7 8 HLA-DOB -500 FLJ45121 -772 LOC440689 -16 MGC52000 -273 FGA -110 C9orf94 -376 LOC389988 -68 STAT2 -94 SH2D3A -273 MLN -740 DPEP1 -765 LOC441906 -496 MGC52000 -466 PPID -384 LOC340501 -32 MMS19L -221 FLJ32949 -500 8D6A -950 LRFN2 -452 FLJ32252 -288 FLG -17 MGC52057 -404 LOC441049 -368 LOC441417 -394 C10orf69 -121 IFNG -795 EIF3S4 -547 C6orf108 -907 FLJ32252 -346 LEP3 -631 MAP1D -120 GPM6A -203 DKFZP434M131 -944 GPR10 -555 MGC26598 -498 RAB3D -852 C6orf108 -907 MGC35212 -360 RAB13 -310 COL3A1 -310 LOC389833 -878 SECISBP2 -404 C10orf93 -42 HAL -358 MGC20983 -338 PLA2G7 -227 FLJ25410 -280 LOC91181 -956 SLC39A10 -921 LOC389833 -288 LOC441453 -821 ASB13 -506 DKFZp434M0331 -920 MGC20983 -338 CRISP1 -236 LOC400506 -715 LOC91181 -956 LOC200726 -220 LOC389833 -288 PHF2 -646 IL15RA -222 LOC400070 -223 MGC20983 -338 CRISP1 -236 LOC94431 -77 LOC126669 -407 IL8RB -447 LOC389833 -878 PHF2 -648 IL15RA -827 TSC -785 NDUFB7 -741 IL17F -733 DOC2A -265 LOC440693 -399 TUBA4 -643 LOC442102 -418 LOC441457 -742 USP6NL -573 GPR109B -392 LOC339377 -660 HMGCLL1 -759 LOC441761 -889 PKLR -118 FLJ25955 -24 FGFBP1 -290 LOC441457 -802 C10orf45 -181 EPIM -568 IL12RB1 -56 LOC442226 -67 LOC57019 -375 PKLR -597 ALPPL2 -296 LOC441013 -188 PRG-3 -971 NMT2 -912 EPIM -568 IL12RB1 -56 C6orf66 -832 ZNF319 -360 FCRH1 -580 UGT1A9 -651 FLJ00310 -289 RAD23B -998 SIAT8F -676 GALNT9 -798 IL12RB1 -56 DJ467N11.1 -34 DNCLI2 -857 SPTA1 -163 UGT1A7 -351 FLJ00310 -881 SLC31A2 -380 NEBL -727 LOC440122 -169 IL12RB1 -56 RTN4IP1 -207 DNCLI2 -857 SLAMF9 -256 UGT1A6 -224 FLJ00310 -289 OR1N2 -646 C10orf52 -163 LOC221140 -342 LOC148198 -361 SLC22A16 -869 DKFZP434A1319 -236 KCNJ10 -383 UGT1A6 -402 FLJ00310 -289 C9orf54 -2 LOC439953 -879 LOC440128 -877 CEBPA -564 LOC442254 -307 LOC439920 -70 ITLN1 -760 TRPM8 -170 FLJ00310 -289 C9orf54 -2 LOC399737 -608 LOC387912 -279 UNQ467 -521 DEADC1 -509 CHST5 -601 ITLN1 -760 ASB1 -723 FLJ00310 -289 LAMC3 -895 CTGLF1 -504 LOC341784 -327 FLJ22573 -941 FLJ44955 -391 CHST5 -756 F11R -798 GCKR -204 FLJ00310 -289 LOC441473 -825 LOC439963 -500 NURIT -947 CLC -823 SYNE1 -484 LOC390748 -242 F11R -798 LOC388938 -212 LOC442127 -287 LOC441473 -825 KCNQ1 -40 RB1 -525 DYRK1B -849 SYNE1 -126 DPH2L1 -42 LMX1A -85 FLJ38348 -606 SRD5A1 -631 LOC441473 -825 LOC387746 -61 DKFZP434K1172 -595 DYRK1B -849 LOC389435 -451 LOC388323 -892 SELP -144 MSH2 -376 LOC345711 -877 DBH -768 OR51F2 -640 DKFZP434K1172 -595 DYRK1B -849 LOC389435 -565 MAP2K4 -128 LOC400796 -263 MSH2 -976 LOC389281 -225 OBP2A -732 TRIM34 -105 LOC144983 -906 PSG11 -297 PIP3-E -457 MAP2K4 -128 F13B -881 MSH2 -376 MGC42105 -669 EGFL7 -330 OR10A2 -851 LOC144983 -892 PSG11 -297 T -9 KRTAP4-12 -78 F13B -881 MSH2 -376 PELO -938 EGFL7 -335 SAA1 -721 LOC144983 -896 PSG4 -299 T -3 JJAZ1 -789 MYOG -951 SBLF -59 BDP1 -918 TRAF2 -32 SAA1 -722 LOC400144 -807 PSG4 -299 LOC442280 -112 CCL2 -912 LOC440712 -956 LOC151443 -85 DKFZp564C0469 -378 LOC441408 -394 LOC441593 -126 PROZ -865 PSG9 -435 DKFZP434J154 -615 PSMB3 -889 LGTN -331 LOC391387 -134 LOC134505 -63 LOC389702 -288 PDHX -845 PROZ -865 FLJ34222 -415 LOC401303 -632 LOC440440 -1 FLJ10874 -676 SEMA4F -751 TSLP -331 C9orf46 -353 TRIM44 -24 CRYL1 -768 ERCC2 -123 LOC441198 -739 FLJ25168 -244 GPATC2 -556 RBM29 -1 LOC340069 -755 SLC24A2 -265 LOC90139 -660 POSTN -32 DMPK -988 GHRHR -646 SP2 -57 LOC440721 -625 LOC339562 -621 SNCAIP -671 IFNA10 -138 NDUFS3 -929 LOC440134 -367 PGLYRP1 -212 ADCYAP1R1 -60 LOC388406 -800 AGT 1 LOC339562 -641 LOC441106 -646 IFNA14 -85 LOC196346 -885 EBPL -973 LIG1 -806 C7orf16 -842 TBX4 -465 FLJ10359 -367 LOC200493 -245 SLC27A6 -484 C9orf11 -311 OR5T3 -97 GUCY1B2 -832 FLJ32926 -288 LOC441209 -41 DDX42 -212 LOC441927 -406 TXNDC9 -714 CDC42SE2 -384 C9orf24 -905 CTNND1 -133 LOC338862 -918 CGB8 -202 GPR154 -435 DDX42 -212 LOC440741 -564 FLJ40629 -946 PHF15 -52 C9orf24 -905 CTNND1 -116 LOC404785 -818 TEAD2 -546 GPR154 -435 LOC90799 -734 MGC12466 -863 LOC401005 -12 LOC389331 -27 UNQ470 -31 CNTF -149 OR11H6 -269 FLJ20643 -895 C7orf36 -707 DKFZP586L0724 -829 KIAA1720 -894 LOC389050 -170 PCDHA4 -26 STOML2 -420 ROM1 -515 C14orf92 -234 LOC400712 -236 BLVRA -400 SSTR2 -874 LOC388578 -522 ORC4L -16 PCDHA4 -26 LOC392334 -904 MARK2 -375 PSMA6 -219 SIGLEC6 -972 BLVRA -400 MRPS7 -822 LOC391205 -430 ORC4L -16 PCDHB3 -623 LOC286327 -215 MARK2 -375 KTN1 -222 SIGLEC6 -972 LOC51619 -311 MRPS7 -719 MIG-6 -618 ORC4L -16 PCDHB6 -212 HNRPK -86 RAB1B -75 C14orf166B -786 SIGLEC6 -972 WBSCR19 -38 LOC388429 -804 MIG-6 -638 ORC4L -16 PCDHB16 -609 LOC441452 -955 GSTP1 -841 EVL -28 ZNF577 -582 LOC136288 -523 NARF -669 MIG-6 -678 ARL5 -895 ABLIM3 -474 DIRAS2 -896 GSTP1 -841 CCNB1IP1 -868 ZNF611 -148 LOC392030 -632 NARF -669 LOC441870 -731 ARL5 -895 LARP -716 LOC286359 -774 LOC440056 -824 CCNB1IP1 -868 ZNF600 -716 FZD9 -485 GEMIN4 -911 LOC440561 -255 NR4A2 -527 LOC134541 -868 TXNDC4 -690 USP35 -148 NEDD8 -143 ZNF600 -37 LOC85865 -255 OR1D2 -376 LOC401940 -500 NR4A2 -527 FGFR4 -472 TXN -239 LOC390231 -471 BAZ1A -508 NALP9 -489 LOC442341 -390 ALOX15 -267 LOC401940 -564 NR4A2 -527 FGFR4 -472 OR1L8 -459 OR4D5 -465 BAZ1A -508 PRDM2 -762 AKR1D1 -159 SLC16A11 -346 LOC401940 -606 NR4A2 -527 FGFR4 -745 DYT1 -561 OR8G5 -809 NFKBIA -963 PRDM2 -762 LOC93432 -126 CLECSF14 -596 LOC339553 -400 ATP5G3 -55 FGFR4 -745 ABO -790 MGC39545 -867 LOC283551 -302 LOC400743 -400 OR2F1 -160 CLECSF14 -640 LOC440753 -695 ZNF533 -598 LOC442145 -7 ABO -789 LOC399969 -328 CDKL1 -902 PADI1 -598 OR2A5 -927 FLJ40217 -393 LOC388789 -593 ZSWIM2 -772 LOC442146 -856 ABO -790 LOC219797 -216 LOC400214 -138 FLJ44952 -494 LOC441184 -336 RCV1 -761 FLJ38374 -686 PGAP1 -821 LOC345462 -604 XPMC2H -374 NUP98 -651 RTN1 -974 DJ462O23.2 -973 LOC441186 -584 CDRT1 -618 LOC391241 -81 PGAP1 -827 LOC345462 -609 LOC441474 -921 NUP98 -651 LOC390488 -457 PPP1R8 5 LOC441187 -654 NOS2A -287 LOC388794 -28 SF3B1 -138 LOC442148 -595 LOC389734 -489 NUP98 -651 PLEK2 -465 PPP1R8 5 LOC389831 -914 NOS2A -287 C20orf70 -431 ORC2L -786 OR2V2 -340 LOC389734 -223 NUP98 -651 PIGH -153 PPP1R8 5 LOC389831 -914 KRT25D -828 STK4 -122 LOC391475 -413 OR2V2 -901 FCN1 -673 KIAA0409 -533 RDH11 -251 ATPIF1 -766 LOC222967 -338 KRT12 -585 PIGT -910 CRYGC -765 TPPP -454 FCN1 -709 LOC283299 -427 FLJ39779 -161 ATPIF1 -766 LOC222967 -338 HUMGT198A -797 DNTTIP1 -479 PECR -942 MYO10 -583 LOC441410 -990 LOC440026 -69 KIAA1509 -179 ATPIF1 -766 LOC340267 -244 HUMGT198A -690 C20orf67 -1 SLC23A3 -412 LOC441066 -463 GAGE1 -21 LOC440030 -675 SERPINA2 -559 LOC440581 -793 ICA1 -699 FLJ31222 -769 MMP9 -875 LOC442070 -877 GDNF -36 RRAGB -788 LOC387754 -159 SERPINA2 -559 CGI-94 -384 AGR2 -65 LOC284058 -524 CEBPB -978 LOC129607 -488 LOC345643 -568 RRAGB -788 LOC144100 -631 SERPINA2 -559 FLJ14351 -753 LOC389472 -184 GIP -957 RNPC1 -370 LOC339789 -268 FOXD1 -990 LOC340527 -194 HPS5 -917 SERPINA9 -856 UROD -715 LOC401316 -837 LOC400619 -823 RNPC1 -370 LOC130502 -558 ARSB -493 SH3BGRL -944 HPS5 -917 LOC390529 -204 LOC441885 -810 CRHR2 -610 UNC13D -695 TH1L -26 ALK -710 DHFR -473 DIAPH2 -921 HPS5 -917 LOC388073 -112 DKFZp761D221 -478 PDE1C -20 LOC339162 -685 TH1L -26 BCL11A -615 SPATA9 -748 DIAPH2 -921 LOC387764 -149 LOC400307 -332 DKFZp761D221 -221 LOC441210 -361 LOC388462 -43 LOC400849 -714 BCL11A -615 CHD1 -581 HSU24186 -145 LOC440041 -221 LOC283694 -71 IL23R -322 LOC222052 -77 SEH1L -801 LOC400849 -382 BCL11A -615 STK22D -863 NXF2 -89 FLJ31393 -362 LOC400320 -443 CTH -6 LOC441224 -287 LOC284232 -988 CGI-09 -309 BCL11A -615 LOC389316 -227 PLP1 -918 OR8H1 -161 FLJ35785 -414 CTH -6 LOC441230 -143 LOC284232 -845 FKHL18 -608 PAP -438 CDO1 -360 PLP1 -918 AGTRL1 -809 LOC440249 -92 AK5 -966 LOC441245 -127 CABLES1 -281 C20orf172 -118 PAP -438 FLJ33977 -166 LOC286436 -713 PRG2 -899 HH114 -991 DNAJB4 -987 LOC441259 -954 CABYR -908 TGM2 -220 PAP -531 LOC391824 -129 SLC6A14 -962 TCN1 -716 PLA2G4B -483 CDC7 -604 CCL26 -441 CABYR -908 TGM2 -220 CNTN4 -809 ALDH7A1 -920 LOC392529 -73 RAB3IL1 -976 CAPN3 -318 LOC388649 -426 SEMA3C -385 CABYR -908 LOC388798 -828 PPARG -584 CAMK2A -429 FLJ25735 -992 KIAA0404 -771 CAPN3 -318 DCLRE1B -406 C7orf23 -761 CABYR -908 Kua-UEV -465 PPARG -914 CAMK2A -429 MAGEB4 -834 CHRDL2 -754 CAPN3 -318 LOC440610 -739 PON1 -785 CABYR -908 Kua-UEV -561 LOC401054 -926 C5orf4 -657 MAGEB4 -834 KCTD14 -94 LOC400368 -320 LOC440610 -584 GATS -36 DSG3 -367 Kua -465 GALNTL2 -427 LOC345430 -332 LOC389844 -822 MRE11A -879 SLC28A2 -275 LOC440610 -652 ACHE -715 SLC14A1 -333 BTBD4 -590 FBXL2 -107 DUSP1 -361 LOC389844 -814 MRE11A -982 DUT -32 LOC441903 -538 ACHE -224 DCC -386 C21orf99 -772 APRG1 -269 LOC285770 -132 UBE1 -964 MMP7 -853 SCG3 -739 LOC440673 -482 ACHE -715 RAB27B -713 C21orf99 -13 APRG1 -347 NQO2 -705 LOC203604 -16 CRYAB -175 LIPC -853 BNIPL -420 ACHE -224 ZCCHC2 -249 KRTAP15-1 -566 LOC440951 -20 MRS2L -22 LOC441481 -796 ZNF202 -527 OSTbeta -781 BNIPL -419 ORC5L -990 LOC342808 -306 B3GALT5 -889 LOC389123 -140 HIST1H2BA -960 DMD -923 LOC387820 -553 LOC440289 -446 SPRR1B -826 ORC5L -990 LOC284276 -397 B3GALT5 -889 LOC285194 -808 HIST1H2BD -597 RPGR 3 LOC387823 -178 COMMD4 -790 SPRR1B -826 CHCHD3 -793 MYOM1 -232 B3GALT5 -889 NR1I2 -769 HIST1H2BD -597 ZNF21 -828 CCND2 -350 LOC400433 -496 IL6R -110 MGC5242 -861 MC2R -113 B3GALT5 -889 STXBP5L -480 HIST1H2BH -618 PRKY -308 NDUFA9 -485 LOC390637 -55 IL6R -110 LOC392997 -596 LOC441817 -600 B3GALT5 -889 LOC442092 -880 HIST1H4I -283 LOC441537 -223 KCNA5 -805 FLJ11175 -113 CKS1B -983 LOC392997 -596 KIAA1632 -405 LOC441955 -824 MRPS22 -897 HLA-H -477 LOC441539 -222 FLJ10665 -245 LOC440224 -815 SYT11 -785 FLJ44186 -168 FBXO15 -123 LOC441955 -824 KCNAB1 -793 MRPS18B -207 LOC441535 -225 FLJ10665 -576 LOC283804 -112 PMF1 -223 HIPK2 -70 FBXO15 -192 LOC400858 -624 LOC402146 -134 LOC401250 -26 LOC441536 -223 LOC285407 -743 CHSY1 -876 LOC164118 -75 ZC3HDC1 -407 LOC390865 -489 CLDN8 -17 LOC90133 -2 LOC401250 -497 LOC338588 -51 LOC390299 -771 LOC440315 -303 FY -397 LOC402301 -14 TXNL4 -33 KRTAP19-7 -127 NLGN1 -541 NFKBIL1 -305 UCN3 -368 FLJ10652 -491 LOC440315 -303 NCSTN -809 BAGE4 -100 CDC34 -270 DSCR1 -620 FLJ20522 -803 LY6G5B -359 NET1 -14 LOC144245 -455 LOC400470 -62 HSPA6 -839 BAGE4 -648 GZMM -678 C21orf84 -232 ATP2B2 -593 C6orf25 -413 MAPK8 -856 PFKM -838 LOC388076 -715 HSPA6 -611 MCPH1 -520 C19orf21 -573 KRTAP12 4 899 LOC440946 917 C6 f25 413 MAPK8 856 DKFZp686O1689 733 LOC440250 206 CGI 01 7 Population prevalence design OtOutcome-sttifidditratified design 0.8 1.0 0.8 1.0 power power 0.4 0.6 0.4 0.6 22 22 0.0 0. 0.0 0.

0 5000 10000 15000 20000 0 500 1000 1500 2000

sample size sample size Population prevalence design OtOutcome-sttifidditratified design

GEscan GEscan 0.8 1.0 0.8 1.0 power power 0.4 0.6 0.4 0.6 22 22 0.0 0. 0.0 0.

0 5000 10000 15000 20000 0 500 1000 1500 2000

sample size sample size