Table S1. Mean Number of Indels and Snvs by Functional Classifications

Home , KRT37, OR7C1, ZNF318, ZNF366

Table S1. Mean Number of Indels and SNVs by Functional Classifications. GAIIx, 1 run GAIIx, 2 runs HiSeq 36 Mb HiSeq 36 Mb GAIIx & HiSeq, 2 runs (n=8) 50 Mb (n=19) 36 Mb (n=3) (n=10) INDELS Filtered, on-target (FOT) variants 1,069 1,202 1,260 2,276 FOT variants passed Quality Filters 1,051 1,192 1,249 2,265 Frameshift 71 76 83 210 Coding 69 78 81 102 Splice-3' 5.1 7.4 7.5 13 Splice-5' 5 5.4 5.6 8.7 UTR-3' 42.5 50.9 54.1 90.5 UTR-5' 18.5 20.3 22.5 36.8 Near-gene-3' 1.4 1.7 1.2 10.5 Near-gene-5' 4.5 4.8 4.4 18.9 Intergenic 6 6.8 6.5 141.2 Intron 846 952 995 1,644 SNVs Total # of SNPs 2,394,617 4,679,679 3,343,458 4,308,699 Filtered, on-target (FOT) variants 24,102 25,232 25,929 37,040 Transition/Transversion Ratio 2.9 2.8 2.8 2.7 FOT variants passed Quality Filters 22,236 23,951 25,187 35,410 Transition/Transversion Ratio 2.9 2.9 2.9 2.7 Nonsense 63.7 62.8 61.3 91.4 Stop gain 54.4 52.4 51.8 67.7 Stop loss 9.3 10.4 9.5 23.8 Splice 22 21.3 22.5 34.5 Coding-Synonymous 8,544 8,903 9,105 10,351 Missense 7,172 7,462 7,689 9,175 Other 8,301 8,783 9,052 17,512

Table S2. Genes with More Than One Missense Variant. Chr Gene Position (rsid) Family 146,461,211 1 NBPF12 146,461,276 (rs71238046) 4 146,466,083 179,642,515 3 2 TTN 179,666,982 (rs35683768) 15 38,753,903 15 3 SCN10A 38,770,119 7 9,361,398 14 4 USP17 9,361,582 16 140,557,779 (rs17844481) 16 5 PCDHB8 140,559,029 (rs73273688) 6 7,583,274 15 DSP 7,585,143 12 6 32,261,014 (rs7751028) C6orf10 5 32,261,653 (rs4947338) 51,152,961 11 COBL 51,203,928 15 7 117,180,174 5 CFTR 117,232,642 (rs1800103) 12 117,243,783 8 12,285,202 8 FAM86B2 12 12,287,930 69,432,667 (rs1924146) 16 9 CCDC29 69,432,706 11 126,678,112 15 126,678,148 15 10 CTBP2 126,682,499 1 126,683,197 1 2,814,356 16 SRRM2 10 2,814,874 45,214,633 45,214,648 45,214,651 17 CDC27 15 45,214,654 45,219,364 45,221,251 (rs1064545) 38,590,731 14 SIPA1L3 38,689,085 15 19 56,243,611 3 NLRP9 56,249,615 12 55,185,563 10 X FAM104B 55,185,656 (rs5003001) 8, 10, 15

Table S3. Private Missense Variants. Chr Position Gene rsID Change 1,267,729 TAS1R3 - LEU,PRO 1,905,557 KIAA1751 - THR,MET 7,887,262 PER3 - SER,ASN 8,926,474 ENO1 rs11544513 ASN,LYS 27,699,991 FCN3 - ARG,TRP 40,125,077 NT5C1A - ILE,VAL 46,651,169 TSPAN1 rs34463133 MET,ILE 89,658,689 GBP4 - ASP,TYR 109,535,450 WDR47,LOC100132742 - ARG,TRP 111,863,044 CHIA - GLY,ARG 119,936,419 HAO2 - VAL,PHE 146,461,211 NBPF12 - LEU,ARG 146,461,276 NBPF12 rs71238046 ALA,PRO 146,466,083 NBPF12 - HIS,TYR 146,493,279 LOC728989 - VAL,ILE 1 146,672,962 FMO5 - ARG,GLY 148,011,037 NBPF14 rs71261063 ASP,HIS 151,261,641 ZNF687 - GLU,LYS 155,295,681 RUSC1 - SER,PHE 173,503,768 SLC9A11 - GLU,ALA 175,365,805 TNR - ARG,GLN 197,111,665 ASPM - ARG,TRP 205,884,508 SLC26A9 - ALA,THR 210,948,886 KCNH1 - GLY,GLU 222,800,921 MIA3 - THR,MET 235,505,965 GGPS1 - ARG,CYS 235,658,082 B3GALNT2 - VAL,MET 235,922,671 LYST - GLU,ALA 236,966,848 MTR rs12749581 ARG,GLN 248,637,544 OR2T3 - ARG,HIS 229,986 SH3YL1 - GLN,ARG 20,251,265 LAPTM4A - PHE,CYS 26,700,309 OTOF - ARG,HIS 27,802,420 C2orf16 - ARG,THR 31,147,616 GALNT14 - PRO,ALA 47,601,029 TACSTD1 - GLN,HIS 48,722,897 CCDC128 - GLY,VAL 55,253,266 RTN4 - PRO,SER 80,529,551 CTNNA2,LRRTM1 - VAL,GLY 99,439,406 C2orf55 - PRO,SER 2 109,102,997 GCC2 - HIS,ASP 131,520,171 FAM123C - SER,THR 141,232,800 LRP1B rs72899872 ALA,THR 166,627,177 GALNT3 - ILE,VAL 179,642,515 TTN - PHE,LEU 179,666,982 TTN rs35683768 ASP,TYR 183,703,257 FRZB - SER,PHE 204,000,845 NBEAL1 - PRO,LEU 220,493,935 SLC4A3 - ARG,GLN 242,501,804 BOK - VAL,MET 13,896,228 WNT7A - THR,ILE 38,753,903 SCN10A - SER,THR 38,770,119 SCN10A - GLU,LYS

42,234,663 TRAK1 - SER,LEU 3 46,414,573 CCR5 rs1800940 ARG,SER 47,448,214 PTPN23 - GLU,LYS 48,638,440 UQCRC1 - GLY,SER 3

49,083,866 QRICH1 - ILE,VAL 50,005,373 RBM6 - PRO,LEU 50,334,462 HYAL3,NAT6 - ARG,TRP 75,713,555 FRG2C rs35781983 ASP,ASN 75,781,243 LOC401074,ZNF717 rs62250085 ILE,VAL 119,886,502 GPR156 - ALA,SER 121,212,545 POLQ - ARG,CYS 183,580,580 PARL - TRP,ARG 185,198,112 MAP3K13 - ASP,GLY 186,331,094 AHSG - GLY,GLU 187,003,786 MASP1 - VAL,MET 187,446,313 BCL6,LOC100131635 - ARG,CYS 197,665,522 IQCG - ARG,TRP 436,848 ZNF721 - LYS,GLU 3,443,769 HGFAC - PRO,LEU 9,361,398 USP17 - GLN,HIS 9,361,582 USP17 - SER,THR 9,405,199 LOC100133128 - ILE,LEU 4 56,820,418 CEP135 - THR,ILE 57,204,798 AASDH - THR,ALA 69,811,110 UGT2A3 rs62641705 TRP,GLY 100,130,075 ADH6 - GLY,VAL 104,030,143 CENPE - LYS,GLN 123,107,254 KIAA1109 - ARG,HIS 5,306,762 ADAMTS16 - PRO,LEU 14,487,587 TRIO - ILE,VAL 23,527,430 PRDM9 - GLU,LYS 32,088,968 PDZD2 - ILE,ARG 33,984,379 SLC45A2 - PRO,SER 34,945,012 DNAJC21 - VAL,MET 56,189,413 MAP3K1 - ARG,GLN 64,050,147 SFRS12IP1 - GLY,ALA 5 71,756,519 ZNF366 - VAL,PHE 111,071,162 C5orf13 - PHE,LEU 112,399,751 MCC - GLY,ARG 140,531,060 PCDHB6 - ASP,ASN 140,557,779 PCDHB8 rs17844481 LEU,PRO 140,559,029 PCDHB8 rs73273688 GLY,ARG 140,764,394 PCDHGA1/2/3/4/5/6/7 - VAL,GLY 145,483,756 PLAC8L1 - ARG,LYS 7,583,274 DSP - GLN,GLU 7,585,143 DSP - GLY,SER 10,529,589 GCNT2 - ASN,ASP 29,429,934 OR2H1 - TYR,HIS 31,595,698 BAT2 - ARG,TRP 32,261,014 C6orf10 rs7751028 GLY,VAL 32,261,653 C6orf10 rs4947338 LEU,TRP 32,548,544 HLA-DRB1 - ILE,LEU 36,931,208 PI16 - PRO,SER

42,713,480 TBCC - ARG,GLN

43,306,461 ZNF318 - LYS,GLU 6 70,981,360 - VAL,ILE COL9A1 74,533,259 CD109 - ARG,CYS 75,814,950 COL12A1 rs34369939 VAL,ALA 87,966,976 ZNF292 - VAL,ALA 89,975,446 GABRR2 - ARG,CYS 90,368,355 MDN1 - PRO,SER 107,420,474 KIAA1553 - PHE,VAL 132,892,017 TAAR6 - CYS,TYR 137,330,503 IL20RA - SER,TYR 137,476,104 IL22RA2 - THR,MET 4

144,750,725 UTRN - VAL,ILE 48,005,000 HUS1 - LEU,PHE 51,152,961 COBL - ARG,GLN 51,203,928 COBL - SER,LEU 77,522,948 PHTF2 - ILE,MET 87,060,844 ABCB4 rs45575636 ARG,GLN 88,965,553 ZNF804B - THR,ILE 98,995,517 PDAP1 - GLU,ALA 99,032,529 PTCD1 rs35556439 ARG,TRP 100,685,280 MUC17 - PRO,LEU 102,120,834 LOC100132214 - SER,PRO 103,835,602 ORC5L - ASP,GLY 7 107,596,043 LAMB1 - ILE,THR 107,684,224 LAMB4 - ILE,VAL 117,180,174 CFTR - ARG,GLN 117,232,642 CFTR rs1800103 ILE,MET 117,243,783 CFTR - MET,THR 117,879,968 ANKRD7 - TYR,HIS 122,338,071 CADPS2,RNF133 - LEU,PRO 124,475,422 POT1 - SER,ARG 129,691,124 ZC3HC1 - THR,ASN 138,851,618 TTC26 rs13225917 ASP,ASN 142,638,473 KEL - ASP,TYR 150,935,385 CSGlcA-T - PRO,LEU 7,808,219 LOC100132396 rs2740676 ILE,LEU 12,285,202 FAM86B2 - ASN,HIS 12,287,930 FAM86B2 - LYS,GLU 28,196,930 PNOC,LOC100129848 - ARG,GLN 37,734,870 RAB11FIP1 - ALA,THR 8 38,265,755 LETM2 - THR,MET 38,374,010 FLJ43582 - HIS,GLN 87,549,792 CPNE3 - ASP,VAL 114,449,045 CSMD3 - GLU,ASP 145,659,016 NFKBIL2 - SER,GLY 19,126,117 ADFP - PRO,LEU 27,548,576 C9orf72 - ILE,THR 32,550,896 TOPORS rs61758066 SER,TRP 35,043,871 C9orf131 - GLU,ASP 39,109,199 CNTNAP3 - GLU,LYS 68,728,863 LOC100132352 - ARG,GLY 9 69,423,521 ANKRD20A4 - ILE,THR 69,432,667 CCDC29 rs1924146 MET,LYS 69,432,706 CCDC29 - GLY,GLU 125,486,365 OR1L4 - LEU,PHE 126,133,160 CRB2 - ARG,TRP 130,914,562 LCN2 - ILE,MET 140,417,276 PNPLA7 - ARG,CYS 4,879,748 AKR1CL2 - LEU,TRP 6,268,177 PFKFB3 - PRO,LEU 29,762,841 SVIL - ARG,TRP

43,326,380 BMS1 - ARG,TRP

51,620,361 TIMM23 - SER,CYS 10 72,358,591 PRF1 - TYR,HIS 85,991,775 LRIT1 - GLU,LYS 90,499,808 LIPK - MET,ARG 95,791,147 PLCE1 - HIS,PRO 96,093,938 NOC3L - HIS,ARG 100,995,498 HPSE2 - CYS,TYR 116,045,781 VWA2 - ARG,TRP 126,682,499 CTBP2 - LYS,ARG 126,683,197 CTBP2 - ILE,MET 5

126,799,611 CTBP2,LOC100132971 - LYS,GLU 134,942,110 GPR123 - ALA,THR 551,708 LRRC56 - THR,MET 702,962 TMEM80 - THR,PRO 799,542 LRDD - ARG,HIS 1,092,760 MUC2 - THR,PRO 1,213,556 MUC5AC rs74046249 ARG,LYS 4,967,540 OR51A4 - ARG,HIS 6,048,408 OR56A1 - CYS,PHE 10,800,639 CTR9 - ASP,VAL 18,568,501 UEVLD - ASP,GLY 32,118,694 RCN1 - ILE,VAL 32,674,734 CCDC73 - ARG,TRP 46,917,560 LRP4 - THR,MET 11 49,598,257 LOC440040 rs7101891 VAL,LEU 55,658,893 SPRYD5 rs34250328 CYS,ARG 62,458,312 BSCL2 - PRO,LEU 65,305,564 SCYL1 - ARG,TRP 66,834,232 RHOD - ARG,TRP 68,478,487 MTL5 - CYS,ARG 74,547,278 RNF169 - GLU,LYS 74,914,359 SLCO2B1 - MET,ILE 89,028,453 TYR - LYS,ASN 92,714,766 MTNR1B - GLY,ASP 104,900,536 CASP1 - ARG,TRP 124,007,900 LOH11CR2A rs73015627 PRO,SER 3,805,977 EFCAB4B - ASP,GLU 3,923,203 PARP11 - GLY,ARG 6,127,833 VWF rs1800386 TYR,CYS 11,506,471 PRB1 - LYS,ARG 21,615,735 PYROXD1 - ASP,GLY 21,624,546 RECQL rs6499 ASP,HIS 12 45,059,357 NELL2 - ARG,CYS 48,886,771 C12orf54 - ARG,GLY 102,046,985 MYBPC1 - GLY,ARG 108,136,105 PRDM4 - LEU,SER 124,824,869 NCOR2 rs61755988 THR,MET 133,365,741 GOLGA3 - ARG,TRP 33,017,503 N4BP2L2 - GLY,ARG 13 113,825,992 PROZ - GLU,VAL 20,528,309 OR4L1 - GLY,CYS 20,585,689 OR4K17 - GLU,LYS 20,711,179 OR11H4 - ALA,PRO 24,607,804 PSME1 - ARG,LYS 14 36,017,741 GARNL1 - HIS,ARG 55,604,883 LGALS3 - GLY,ARG 70,175,690 KIAA0247 rs45544938 VAL,GLY 93,275,714 GOLGA5 rs34515753 ARG,GLN 96,781,723 ATG2B - LYS,GLU 24,922,053 C15orf2 rs34629208 ASP,TYR 48,713,794 FBN1 - ARG,TRP

57,820,876 CGNL1 - ARG,TRP 15 69,732,770 KIF23 - ARG,TRP

75,798,027 PTPN9 - PHE,LEU

86,283,483 AKAP13 - GLU,LYS 90,168,736 C15orf42 - THR,MET 101,718,677 CHSY1 - MET,THR 2,814,356 SRRM2,LOC100132779 - GLU,GLY 2,814,874 SRRM2,LOC100132779 - ASP,HIS 16 21,245,101 ANKS4B - GLU,GLN 22,826,241 HS3ST2 - SER,PRO 6

23,701,251 PLK1 - ARG,HIS 30,364,505 CD2BP2 - MET,ILE 4,098,747 ANKFY1 - ILE,VAL 4,540,514 ALOX15 - GLY,ARG 7,762,859 CYB5D1 - LEU,PHE 7,839,694 CNTROB rs61747003 ARG,LEU 7,910,817 GUCY2D rs61749682 LEU,PHE 7,948,239 ALOX15B - LEU,PHE 17,127,274 FLCN - ARG,TRP 18,653,403 FBXW10 - ASP,ASN 19,684,338 ULK2 - LYS,GLU 20,799,166 MGC87631 - ASN,LYS 27,023,927 SUPT6H - MET,LEU 27,182,060 ERAL1 - ALA,GLY 31,351,014 ACCN1 rs16967895 ASP,GLY 36,485,118 GPR179 - ALA,VAL 39,240,745 LOC100132476 - LYS,ARG 39,274,206 LOC653240 - ARG,LYS 17 39,421,886 LOC732428 rs12938692 TYR,CYS 39,535,855 KRT34 - ASN,LYS 39,577,715 KRT37 rs62066785 ARG,LEU 45,214,633 CDC27 - TYR,ASP 45,214,648 CDC27 - GLN,GLU 45,214,651 CDC27 - ILE,LEU 45,214,654 CDC27 - ALA,THR 45,219,364 CDC27 - MET,ARG 45,221,251 CDC27 rs1064545 LYS,GLU 65,739,626 NOL11 - ALA,VAL 66,981,048 ABCA9 - PRO,THR 67,146,149 ABCA10 - ARG,TRP 73,501,926 CASKIN2 - ARG,TRP 73,624,353 RECQL5 - ASN,THR 74,005,802 EVPL - GLU,LYS 76,967,770 LGALS3BP,LOC100133045 - ASP,ALA 76,993,154 CANT1 - THR,MET 34,398,883 C18orf10 rs2303507 ARG,CYS 18 56,246,930 ALPK2 - ASP,ASN 14,877,085 EMR2 - PRO,LEU 16,060,577 OR10H4 - TYR,HIS 19,312,523 RFXANK,NR2C2AP - GLU,LYS 19,656,185 CILP2 - LYS,THR 20,135,109 ZNF682 rs61746244 SER,ASN 20,308,232 ZNF486 - TYR,CYS 30,193,654 C19orf12 - LYS,GLU 33,149,861 ANKRD27 - ARG,CYS 35,450,031 ZNF792 - GLY,VAL 19 36,278,187 SNX26 - ARG,GLN 38,590,731 SIPA1L3 - ARG,TRP

38,689,085 SIPA1L3 - ARG,CYS

39,406,338 SARS2 - ARG,TRP

41,631,417 CYP2F1 - LEU,PRO 42,603,716 POU2F2 - LEU,PRO 44,981,304 ZNF180 - TYR,CYS 46,137,712 EML2 - ARG,GLN 49,113,244 FAM83E rs71357835 ARG,HIS 49,227,611 RASIP1 - ARG,CYS 53,612,490 ZNF415 - LYS,GLU 55,148,214 LILRB1 - THR,ILE 55,325,450 KIR2DL4 rs35946789 ALA,PRO 55,740,069 TMEM86B - CYS,PHE 56,243,611 NLRP9 - SER,ILE 7

56,249,615 NLRP9 - ILE,MET 57,325,545 PEG3,ZIM2 rs56237501 ALA,GLY 57,889,494 ZNF547 - GLY,ARG 17,617,260 RRBP1 - ARG,TRP 20 40,050,639 CHD6 - ARG,TRP 44,469,366 SNX21 rs35599678 HIS,PRO 31,802,630 KRTAP13-4 - ARG,CYS 35,742,799 KCNE2 rs2234916 THR,ALA 21 40,552,341 PSMG1 - MET,THR 43,531,731 UMODL1 - THR,MET 43,896,050 RSPH1 - ARG,TRP 46,047,543 C21orf29,KRTAP10-9 - ALA,VAL 18,609,211 TUBA8 - ARG,CYS 22,842,664 ZNF280B rs41277495 THR,ALA 23,524,268 BCR - SER,TRP 24,896,179 UPB1 - ARG,PRO 25,045,900 LOC644165 - ARG,TRP 29,661,524 RHBDD3 - VAL,GLY 22 31,011,350 TCN2 rs35838082 ARG,TRP 31,536,074 PLA2G3 rs55984643 HIS,GLN 32,554,994 RP1-127L4.6 - PRO,LEU 38,165,136 TRIOBP - ARG,HIS 43,032,758 CYB5R3 - PRO,LEU 43,525,273 BIK - PRO,ALA 43,529,323 MCAT - ASN,SER 3,239,708 MXRA5 - ASP,ASN 48,544,153 WAS - GLU,LYS 54,784,246 ITIH5L rs41306886 THR,MET 55,185,656 FAM104B rs5003001 ARG,ILE X 100,400,154 CENPI - PHE,SER 123,215,296 STAG2 - ILE,VAL 135,314,244 MAP7D3 - PRO,LEU 135,428,755 GPR112 - GLU,LYS 152,807,810 ATP2B3 rs62642960 ILE,LEU

Table S4. Private Indel Variants. Chr Position Gene Ref/Alt Family 19,597,274 AFAR3 C/- 8 40,981,245 C1orf176 -/G 11 1 148,591,267 NBPF15 TCAACTCCTTC/- 12 248,685,789 OR2G6 -/C 3 2 196,661,361 DNAH7 C/- 12 46,414,943 CCR5 ACAGTCAGTATCAATTCTGGAAGAATTTCCAG/- 1 66,430,818 LRIG1 CG/- 15 3 149,238,595 WWTR1 -/TTAA 6 178,960,766 KCNMB3 T/- 16 4 57,204,689 AASDH -/TT 1 179,740,917 GFPT2 G/- 15 5 180,477,253 BTNL9 C/- 10 26,184,042 HIST1H2BE C/- 10 32,370,969 BTNL2 G/- 10 6 32,551,958 HLA-DRB1 -/TT 16 32,609,296 HLA-DQA1 -/G 11 32,609,298 HLA-DQA1 A/- 11 15,601,409 TMEM195 -/AA 12 7 128,587,366 IRF5 ACTCTGCGGCCGCCT/- 12 8 52,732,972 PCMTD1 -/T 4 6,329,010 TPD52L3 G/- 5 9 43,844,264 CNTNAP3B G/- 16 4,594,558 C11orf40 -/G 14 55,861,277 OR8I2 T/- 12 11 56,128,673 OR8J1 -/T 10 58,170,792 OR5B3 G/- 16 64,543,927 SF1 -/T 2 12 70,088,219 BEST3 T/- 2 15 75,798,025 PTPN9 G/- 3 16 336,700 PDIA2 CT/- 12 27,893,565 LOC116236 A/- 6 39,183,011 KRTAP1-5 G/- 7 17 39,197,440 KRTAP1-1 C/- 14 43,112,231 DCAKD CT/- 6 56,233,444 OR4D1 -/T 1 14,910,637 OR7C1 A/- 4 15,053,008 OR7C2 -/T 4 15,166,025 CASP14 AC/- 4 19 16,003,336 CYP4F2 A/- 4 48,735,017 CARD8 -/TT 1 51,729,103 CD33 CCGG/- 14 23,967,141 GGTLC1 C/- 10 20 34,215,234 CPNE1 -/A 12 22 18,072,864 SLC25A18 CT/- 13

Table S5. Genes with More Than One Variant in Families Predicted to be Recessive. Family Gene # Variants 2 CEACAM3 2 CTBP2 3 LPA 2 MAGEB16 2 PDE4DIP 2 3 BCL8 2 PTPN9 2 PYROXD1 2 6 PCDHB17 2 RACGAP1P 6 ZNF717 5 11 BAGE2,BAGE3,BAGE4,BAGE5 2 CXADRP3 2 DDX12 2 FAM104B 2 FKBP9L 2 HLA-DQA1 2 TRHDE 3 LOC642236 2 LOC642846 4 MAGEB18 2 MST1P2 4 MST1P9 2 MUC2 2 NBPF10 2 NBPF9 2 ROCK1P1 2 SIGLEC16 2 TRIM71 2 ZNF717 2 13 CYP2D7P1 2 GGT3P 2 KIR3DL3 2 KRTAP5-4 2 MAGEB16 2 MAP2K 2 MED12 2 NBPF10 2 NUDT10 3 POLA1 4 TPM2 3

Table S6. Linkage of Validated Variants. Family Gene Max NPL observed/maximum pValue LOD LOD NPL score

1 SLC5A11 1.81 0.60 33.15 0.05 1 ADH6 1.76 0.53 30.11 0.06 1 CENPE 1.76 0.50 28.41 0.06 1 TMC2 1.76 -0.11 -6.25 0.80 2 AHSG 1.81 0.70 38.67 0.04 2 MASP1 1.81 0.63 34.81 0.04 2 PNPLA5 1.81 0.28 15.47 0.13 2 C6orf170 1.81 0.22 12.15 0.20 3 PTPN9 2.41 -0.18 -7.47 0.80 16 RPGRIP1 0.60 0.15 25.00 0.20 16 LGALS14 0.60 0.03 5.00 0.40 16 KIF23 2.41 -0.11 -4.56 0.80 12 ZNF440 0.60 0.24 40.00 0.15 12 TNFRSF19 0.60 0.23 38.33 0.20

Table S7. Variants identified in Hereditary Colon Cancer Genes. Gene rsID DNA AA Change Classification ESP MAF Family change (EA) APC rs67622085 T/A Pro/Pro Synonymous 1.4% 11 AXIN2 rs149089442 G/A - Intronic 0.8% 4 BRCA1 rs1799950 T/C Gln/Arg Missense 6.4% 15 rs766173 A/C Asn/His Missense 3.7% 12 rs1766644 A/G Asn/Asp Missense 3.7% 12 rs4987117 C/T Thr/Met Missense 2.9% 10 BRCA2 rs1801439 A/G Ser/Ser Synonymous 3.7% 12 rs11571651 G/T - Intronic 3.6% 12 rs1801499 T/C His/His Synonymous 3.7% 12 GALNT12 rs2273846 G/C Ser/Ser Synonymous 5.2% 2 rs151039584 C/G Gly/Arg Missense 0.6% 13 MCC rs7726162 A/C - Intronic 54.2%* 8, 11, 12, 14, 15 MYH11 rs880071 G/A Ser/Ser Synonymous 6.7% 16 rs1805321 G/A Pro/Ser Missense 42.1% 5, 6 PMS2 rs1802683 C/G Gly/Ala Missense 17.3%* 9 TP53 rs1800370 C/T Pro/Pro Synonymous 1.5% 2 No variants of any type were identified in: AKT1, AXIN1, BLM, BMPR1A, CHEK2, MLH1, MLH2, MLH3, MSH2, MSH3, MSH6, MUTYH, PMS1, PTEN, SMAD4, SMAD7, STK11, TGFB1, and TGFBR2. *Variant was not found in the ESP database; MAF reported was from the 1000 Genomes Project for Caucasians.

Table S8. Genes with Shared Variants in Previously Reported Linkage Regions Dom 1-HLOD Position DNA AA Variant Cytoband HLOD rsID Gene Family Range (Mb) (Build 37) change change Type Score 77,660,829 rs73826426 SHROOM3 C/A TYR/Stop Nonsense 8, 10 74,270,822 - ALB C/T None Intronic 16 4q21.1 4.51 73.8 – 83.3 75,065,702 - MTHFD2L G/A None Intronic 11 75,482,263 rs1494868 AREG A/G None Intronic 8, 13, 16 77,292,744 - CCDC158 A/C None Intronic 6 57,820,876 - CGNL1 C/T ARG/TRP Missense 10 69,732,770 - KIF23 C/T ARG/TRP Missense 16 59,387,344 - RNF111 G/C None/UTR UTR 10 15q22.31 3.07 55.4 – 68.5 59,515,195 - MYO1E T/C None Intronic 4 63,930,778 - HERC1 C/T None Intronic 16 64,692,931 - TRIP4 C/G None Intronic 4 65,682,474 - IGDCC4 T/C None Intronic 4

Table S9. Genes with Shared Variants in Family-Specific Linkage Peaks Family Chr Dom 1-HLOD Position rsID Gene DNA AA Variant HLOD Range (Build 37) change change Type Score (Mb) 1 4 1.44 81.6 - 100,130,075 - ADH6 C/A GLY/VAL Missense 156.0 104,030,143 - CENPE T/G LYS/GLN Missense 2 1 1.86 89.9 – 109,535,450 - WDR47 C/T ARG/TRP Missense 111.1 3 1.50 172.8 – 186,331,094 - AHSG G/A GLY/GLU Missense 198.8 187,003,786 - MASP1 C/T VAL/MET Missense 178,952,181 - PIK3CA T/C None UTR-3’ 9 1.70 76.4 – 91.8 84,300,733 - TLE1 A/C None Intronic 82,191,137 - TLE4 G/T None Intronic 90,388,188 rs35063649 CTSL3 C/T None Intronic 91,727,427 - SHC3 C/A None Intronic 3 9 1.34 14.6 – 23.2 19,096,666 - HAUS6/FAM29A C/G None Intergenic 20,493,700 - CDRT15L2/CCFC144NL A/C None Intronic 17 1.56 13.1 – 28.6 29,588,886 - NF1 A/G None Intronic 29,646,045 - NF1/EVI2A T/A None Intronic 4 15 2.43 25.9 – 69.3 41,067,721 - DNAJC17 A/C None Intronic 43,888,774 - CKMT1B A/T None Intronic 59,515,195 - MYO1E T/C None Intronic 64,692,931 - TRIP4 C/G None Intronic 65,682,474 - IGDCC4 T/C None Intronic 5 7 1.34 104.6 – 117,180,174 - CFTR G/A ARG/GLY Missense 131.6 129,691,124 - ZC3HC1 G/T THR/ASN Missense 9 1.32 2.2 – 6.1 5,339,799 rs2273784 RLN1 G/A None UTR-5’ 10 1.32 128.0 – 134,039,023 - STK32C G/T None Intronic 134.9

Table S10. Variants in Identified GWAS Regions. Chr SNP Nonsense, Splice-Site Missense Synonymous, Non-coding rs6691170, 1 - - DUSP10 (rs11118830) rs6687758 3 rs10936599 - - LRRC31 (rs41273579) BRPF3 (rs45504893) PNPLA1 (rs41270096) C6orf222 (no rsID) STK38 (rs55921013) STK38 (no rsID) CDKN1A (rs1059234) CDKN1A (rs1801270) PPIL1 (no rsID) 6 rs1321311 - PI16 (no rsID) PI16 (rs41272196) - MTCH1 (rs11548576) - MTCH1 (no rsID) - FGD2 (no rsID) BAGE,BAGE2,BAGE3,BAGE4,BAGE5 (rs1752238) LPA (no rsID) LPA (no rsID) 6 rs7758229 - - LPA (no rsID) LPA (rs41267831) PLG (rs3798222) PLG (rs3798222) rs6983267, 8 rs7014346, - - MYC (rs2070582) rs10505477 C11orf92 (no rsID) 11 rs3802842 - - POU2AF1 (rs11213848) RNF169 (no rsID) 11 rs3824999 - RNF169 (no rsID) RNF169 (no rsID) NEU3 (no rsID) LARP(rs17124706) 12 rs11169552 - FAM130A1 (rs4768957) DIP2B (no rsID) 15 rs4779584 - - FMNT (rs11637012) 18 rs4939827 - CTIF (rs2277712) - ANKRD27 (no rsID) CEP89 (no rsID) TDRD12 (rs73579706) CEP89/CCDC123 (no rsID) CCDC123 (no rsID) WDR88 (rs73039475) 19 rs10411210 - CCDC123 (rs73035551) PEPD (rs3745969) CCDC123 (rs28626308) - RHPN2 (no rsID) - MCM8 (no rsID) MCM8 (rs35180674) 20 rs961253 - MCM8 (rs61754763) FERMT1 (rs6076938) FERMT1 (rs55666319) FERMT1 (no rsID) ADRM (rs11544169) CDH4 (rs3761221) LAMA5 (rs41307205) LSM14B (rs4925345) LAMA5 (no rsID) SS18L1 (rs60991008) - SS18L1 (rs61744430) - SS18L1 (rs73309164) 20 rs4925386 ADRM1/LAMA5 (rs2427279) - OSBPL2 (no rsID) - LAMA5 (rs944897) - LAMA5 (rs2427281) - CABLES2 (rs13042761) - SLCO4A1 (no rsID) TBL1X (rs2301675) X rs5934683 - - TBL1X (rs3747430) WWC3 (rs6530368)

No variants were found in the regions surrounding rs16892766 (Chr8), rs10795668 (Chr10), rs7315438 (Chr12), rs4444235 (Chr14), or rs9929218 (Chr16).

Table S11. Expected and Observed Shared Variants. Expected Sharing Observed Sharing p† Family Shared Observed Expected Sharing O/E Sharing 10 Nonsense 0.20 1.38 0.202 Missense 0.19 1.36 <0.001 0.14 Indels 0.46 3.19 <0.001 Synonymous & Non-coding 0.03 0.18 <0.001 12 Nonsense 0.16 1.15 0.568 Missense 0.25 1.74 <0.001 0.14 Indels 0.54 3.77 <0.001 Synonymous & Non-coding 0.03 0.19 <0.001 14 Nonsense 0.24 1.71 0.007 Missense 0.21 1.46 <0.001 0.14 Indels 0.42 2.93 <0.001 Synonymous & Non-coding 0.02 0.17 <0.001 15 Nonsense 0.26 1.80 0.004 Missense 0.21 1.48 <0.001 0.14 Indels 0.36 2.55 <0.001 Synonymous & Non-coding 0.03 0.19 <0.001 2 Nonsense 0.23 2.08 0.008 Missense 0.18 1.66 <0.001 0.11 Indels 0.35 3.16 <0.001 Synonymous & Non-coding 0.02 0.14 <0.001 3 Nonsense 0.06 0.54 0.188 Missense 0.14 1.23 0.003 0.11 Indels 0.29 2.61 <0.001 Synonymous & Non-coding 0.01 0.11 <0.001 5 Nonsense 0.12 1.09 0.821 Missense 0.18 1.64 <0.001 0.11 Indels 0.38 3.48 <0.001 Synonymous & Non-coding 0.01 0.13 <0.001 6 Nonsense 0.16 1.41 0.272 Missense 0.16 1.45 <0.001 0.11 Indels 0.37 3.39 <0.001 Synonymous & Non-coding 0.01 0.12 <0.001 16 Nonsense 0.29 2.61 <0.001 Missense 0.23 2.11 <0.001 0.11 Indels 0.55 4.99 <0.001 Synonymous & Non-coding 0.04 0.33 <0.001

Table S11. Expected and Observed Shared Variants, continued. Expected Sharing Observed Sharing p† Family Shared* Observed Expected Sharing O/E Sharing 1 Nonsense 0.09 1.29 0.629 Missense 0.12 1.73 <0.001 0.07 Indels 0.37 5.49 <0.001 Synonymous & Non-coding 0.01 0.17 <0.001 11 Nonsense 0.19 2.88 <0.001 Missense 0.16 2.33 <0.001 0.07 Indels 0.36 5.37 <0.001 Synonymous & Non-coding 0.02 0.32 <0.001 13 Nonsense 0.18 2.64 <0.001 Missense 0.17 2.60 <0.001 0.07 Indels 0.45 6.69 <0.001 Synonymous & Non-coding 0.02 0.33 <0.001 4 Nonsense 0.03 0.93 0.994 Missense 0.10 3.22 <0.001 0.03 Indels 0.42 13.12 <0.001 Synonymous & Non-coding 0.01 0.36 <0.001 8 Nonsense 0.10 4.65 <0.001 Missense 0.05 2.13 <0.001 0.02 Indels 0.25 11.43 <0.001 Synonymous & Non-coding 0.01 0.43 <0.001 7 Nonsense 0.07 3.38 <0.001 Missense 0.05 2.50 <0.001 0.02 Indels 0.23 11.49 <0.001 Synonymous & Non-coding 0.00 0.23 <0.001 9 Nonsense 0.11 5.26 <0.001 Missense 0.07 3.57 <0.001 0.02 Indels 0.27 13.37 <0.001 Synonymous & Non-coding 0.01 0.60 <0.001 *Calculated as 1-[(2D+1-2)/(2D+1-1)], modified from (49) †Chi-squared Goodness of Fit