Background
Methods
Candidate genes
SNP | GWAS proposed candidates | Neighbouring genes ± 500 kb | SNP | GWAS proposed candidates | Neighbouring genes ± 500 kb |
---|---|---|---|---|---|
rs7726159 |
TERT
| – | rs2016394 | – |
DLX2
|
rs10069690 |
TERT
| – | rs1550623 |
CDCA7
| – |
rs2736108 |
TERT
| – | rs6762644 | – | SETMAR; ITPR1 |
rs2588809 |
RAD51B
| – | rs12493607 |
TGFBR2
| – |
rs999737 |
RAD51B
| – | rs9790517 |
TET2
| – |
rs10759243 | – |
RAD23B
| rs6828523 |
ADAM29
| – |
rs2981579 |
FGFR2
| – | rs1353747 |
PDE4D
| – |
rs11199914 | – |
FGFR2
| rs1432679 |
EBF1
| – |
rs7072776 |
DNAJC1
| – | rs204247 |
RANBP9
| – |
rs11814448 |
DNAJC1
| – | rs720475 | – |
TPK1
|
rs13387042 | – |
TNP1
| rs6472903 | – |
HNF4G
|
rs11552449 | – |
DCLRE1B
| rs2943559 |
HNF4G
| – |
rs1045485 |
CASP8
| – | rs7904519 |
TCF7L2
| – |
rs4973768 |
SLC4A7
| – | rs3903072 | – | KAT5; SNX32; MUS81 |
rs889312 |
MAP3K1
| – | rs11820646 | – |
NFRKB
|
rs12662670 |
ESR1
| – | rs2236007 |
PAX9
| – |
rs2046210 |
ESR1
| – | rs941764 |
CCDC88C
| – |
rs1011970 | CDKN2A; CDKN2B | – | rs17817449 |
FTO
| – |
rs704010 |
ZMIZ1
| – | rs13329835 |
CDYL2
| – |
rs3817198 |
LSP1
| – | rs527616 | – |
CHST9
|
rs10771399 |
PTHLH
| – | rs1436904 |
CHST9
| – |
rs3803662 |
TOX3
| – | rs4808801 |
ELL
| – |
rs6504950 |
COX11
| – | rs3760982 | – | XRCC1; KCNN4; ZNF283; ZNF226 |
rs8170 | – | USHBP1; BABAM1; UNC13A | rs132390 | – | EMID1; NF2 |
rs2363956 | – | USHBP1; BABAM1; UNC13A | rs6001930 |
MKL1
| – |
rs2823093 |
NRIP1
| – | rs4245739 |
MDM4
| – |
rs616488 |
PEX14
| – | rs6678914 |
LGR6
| – |
rs4849887 | – |
EPB41L5
| rs11075995 |
FTO
| – |
Cohorts
Targeted sequencing, variant calling and variant filtering
Statistical analysis
Results
Loss-of-function variants
Symbol | CDS changea | Protein change | dbSNP identifier | Cases | Control participants | Consequence | EVS European MAF | ExAC non-Finnish European MAF |
---|---|---|---|---|---|---|---|---|
ADAM29
| c.2020A > T | p.Lys674Ter | – | 1 | 0 | Stop-gained | 0 | 0 |
CASP8
| c.379C > T | p.Arg127Ter | – | 1 | 0 | Stop-gained | 0 | 0 |
CDKN2A
| c.225_243delCGCCACTCTCACCCGACCC | p.Ala76CysfsTer64 | – | 1 | 0 | Frame shift | 0 | 0 |
CDKN2B
| c.149_150delCG | p.Ala50AspfsTer36 | – | 0 | 1 | Frame shift | 0 | < 0.0001 |
DCLRE1B
| c.189 + 1G > C | – | 1 | 0 | Splice donor | 0 | 0 | |
DCLRE1B
| c.256G > T | p.Gly86Ter | – | 0 | 1 | Stop-gained | 0 | 0 |
FTO
| c.11delC | p.Pro5ArgfsTer13 | – | 1 | 0 | Frame shift | 0 | 0 |
LGR6
| c.858-2A > C | – | 1 | 0 | Splice acceptor | < 0.0001 | < 0.0001 | |
MUS81
| c.1314delC | p.Pro439LeufsTer6 | – | 1 | 0 | Frame shift | 0 | 0 |
MUS81
| c.1062delC | p.Arg355GlyfsTer2 | – | 0 | 1 | Frame shift | 0 | 0 |
NFRKB
| c.2149G > T | p.Glu717Ter | – | 1 | 0 | Stop-gained | 0 | 0 |
NFRKB
| c.794C > G | p.Ser265Ter | – | 0 | 1 | Stop-gained | 0 | < 0.0001 |
NRIP1
| c.40_41insT | p.Asp14ValfsTer25 | – | 1 | 0 | Frame shift | 0 | 0 |
NRIP1
| c.2750C > G | p.Ser917Ter | – | 1 | 0 | Stop-gained | 0 | 0 |
NRIP1
| c.1968dupT | p.Gly657TrpfsTer5 | – | 1 | 0 | Frame shift | 0 | 0 |
PDE4D
| c.2400_2410dupTGTCATAGATG | p.Asp804ValfsTer3 | – | 1 | 0 | Frame shift | 0 | 0 |
RAD51B
| c.139C > T | p.Arg47Ter | rs200355697 | 2 | 0 | Stop-gained | 0 | 0.0001 |
SETMAR
| c.823_826delAAAG | p.Glu276GlyfsTer2 | – | 1 | 0 | Frame shift | 0 | < 0.0001 |
SETMAR
| c.706C > T | p.Arg236Ter | – | 0 | 1 | Stop-gained | 0 | 0.0001 |
SETMAR
| c.1635C > G | p.Tyr545Ter | – | 0 | 1 | Stop-gained | 0 | 0 |
SLC4A7
| c.1663G > T | p.Gly555Ter | – | 1 | 0 | Stop-gained | 0 | 0 |
SNX32
| c.1111C > T | p.Arg371Ter | – | 1 | 0 | Stop-gained | 0 | < 0.0001 |
SNX32
| c.825 + 2 T > G | – | 1 | 0 | Splice donor | 0 | 0 | |
TCF7L2
| c.1804_1805insAAT | p.Glu602_Glu603insTer | – | 0 | 1 | Stop-gained | 0 | 0 |
TET2
| c.1085_1086insT | p.Pro363SerfsTer6 | – | 1 | 0 | Frame shift | 0 | 0 |
TET2
| c.2072delC | p.Thr691MetfsTer9 | – | 1 | 0 | Frame shift | 0 | 0 |
TET2
| c.3646C > T | p.Arg1216Ter | – | 1 | 0 | Stop-gained | 0 | 0 |
TET2
| c.4361_4362insG | p.Arg1455GlnfsTer23 | – | 1 | 0 | Frame shift | 0 | 0 |
TET2
| c.3812_3820delGCGCCTGTC | p.Cys1271_Gln1274delinsTer | – | 1 | 0 | Stop-gained | 0 | 0 |
TET2
| c.832C > T | p.Gln278Ter | – | 0 | 1 | Stop-gained | 0 | 0 |
TET2
| c.1458delC | p.Asn486LysfsTer11 | – | 0 | 1 | Frame shift | 0 | 0 |
TPK1
| c.185 + 1G > A | – | 0 | 1 | Splice donor | 0 | 0 | |
USHBP1
| c.1220 + 1G > T | rs144791770 | 1 | 0 | Splice donor | 0.0002 | 0.0001 | |
USHBP1
| c.258dupA | p.Val87SerfsTer103 | – | 0 | 1 | Frame shift | 0.0001 | < 0.0001 |
ZNF226
| c.1229_1230delAA | p.Arg411SerfsTer11 | – | 1 | 0 | Frame shift | 0 | 0.0001 |
ZNF226
| c.2239C > T | p.Arg747Ter | – | 1 | 0 | Stop-gained | 0 | 0 |
ZNF226
| c.2380G > T | p.Glu794Ter | rs201830106 | 0 | 1 | Stop-gained | 0.0007 | 0.0003 |
ZNF226
| c.582delT | p.Asn194LysfsTer41 | – | 0 | 1 | Frame shift | 0 | 0 |
Gene | Selection criteria | Number of carriers with loss-of-function variants | Number of carriers with missense variants | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Case | Control | p Valuea | OR | 95% CI | Case | Control | p Valuea | OR | 95% CI | ||
TET2
| GWAS proposed | 5 | 2 | 0.456 | 2.27 | 0.37–23.87 | 20 | 18 | 1 | 1.01 | 0.50–2.03 |
NRIP1
| GWAS proposed | 3 | 0 | 0.251 | Und | 0.37–∞ | 21 | 17 | 0.632 | 1.12 | 0.56–2.28 |
RAD51B
| GWAS proposed | 2 | 0 | 0.501 | Und | 0.17–∞ | 6 | 4 | 0.756 | 1.36 | 0.32–6.57 |
SNX32
| Neighbouring genes | 2 | 0 | 0.501 | Und | 0.17–∞ | 3 | 6 | 0.323 | 0.45 | 0.07–2.12 |
ZNF226
| Neighbouring genes | 2 | 2 | 1 | 0.91 | 0.07–12.5 | 24 | 18 | 0.640 | 1.21 | 0.63–2.39 |
ADAM29
| GWAS proposed | 1 | 0 | 1 | Und | 0.02–∞ | 13 | 11 | 1 | 1.07 | 0.44–2.65 |
CASP8
| GWAS proposed | 1 | 0 | 1 | Und | 0.02–∞ | 8 | 2 | 0.113 | 3.64 | 0.72–35.26 |
CDKN2A
| GWAS proposed | 1 | 0 | 1 | Und | 0.02–∞ | 3 | 3 | 1 | 0.91 | 0.12–6.77 |
DCLRE1B
| Neighbouring genes | 1 | 1 | 1 | 0.91 | 0.01–71.08 | 7 | 6 | 1 | 1.06 | 0.30–3.82 |
FTO
| GWAS proposed | 1 | 0 | 1 | Und | 0.02–∞ | 10 | 11 | 0.668 | 0.82 | 0.31–2.14 |
LGR6
| GWAS proposed | 1 | 0 | 1 | Und | 0.02–∞ | 16 | 8 | 0.217 | 1.82 | 0.73–4.94 |
MUS81
| Neighbouring genes | 1 | 1 | 1 | 0.91 | 0.01–71.08 | 8 | 9 | 0.808 | 0.80 | 0.27–2.36 |
NFRKB
| Neighbouring genes | 1 | 1 | 1 | 0.91 | 0.01–71.08 | 17 | 12 | 0.577 | 1.29 | 0.58–2.97 |
PDE4D
| GWAS proposed | 1 | 0 | 1 | Und | 0.02–∞ | 6 | 3 | 0.512 | 1.81 | 0.39–11.24 |
SETMAR
| Neighbouring genes | 1 | 2 | 0.607 | 0.45 | 0.01–8.70 | 7 | 3 | 0.349 | 2.12 | 0.48–12.73 |
SLC4A7
| GWAS proposed | 1 | 0 | 1 | Und | 0.02–∞ | 14 | 10 | 0.682 | 1.27 | 0.52–3.21 |
USHBP1
| Neighbouring genes | 1 | 1 | 1 | 0.91 | 0.01–71.08 | 14 | 11 | 0.841 | 1.15 | 0.48–2.82 |
CDKN2B
| GWAS proposed | 0 | 1 | 0.475 | 0 | 0–35.30 | 1 | 1 | 1 | 0.91 | 0.01–71.08 |
TCF7L2
| GWAS proposed | 0 | 1 | 0.475 | 0 | 0–35.30 | 5 | 8 | 0.406 | 0.56 | 0.14–1.96 |
TPK1
| Neighbouring genes | 0 | 1 | 0.475 | 0 | 0–35.30 | 2 | 2 | 1 | 0.91 | 0.07–12.50 |
ZNF283
| Neighbouring genes | – | – | – | – | – | 17 | 6 | 0.057 | 2.59 | 0.97–8.06 |
HNF4G
| GWAS proposed | – | – | – | – | – | 4 | 1 | 0.377 | 3.63 | 0.36–178.82 |
TERT
| GWAS proposed | – | – | – | – | – | 5 | 6 | 0.765 | 0.75 | 0.18–2.97 |
UNC13A
| Neighbouring genes | – | – | – | – | – | 17 | 8 | 0.158 | 1.94 | 0.79–5.21 |
LSP1
| GWAS proposed | – | – | – | – | – | 11 | 15 | 0.327 | 0.66 | 0.27–1.55 |
XRCC1
| Neighbouring genes | – | – | – | – | – | 6 | 12 | 0.153 | 0.45 | 0.14–1.30 |
ZMIZ1
| GWAS proposed | – | – | – | – | – | 15 | 11 | 0.694 | 1.24 | 0.53–3.00 |
EMID1
| Neighbouring genes | – | – | – | – | – | 11 | 8 | 0.654 | 1.25 | 0.46–3.59 |
FGFR2
| GWAS proposed | – | – | – | – | – | 4 | 4 | 1 | 0.91 | 0.17–4.87 |
CCDC88C
| GWAS proposed | – | – | – | – | – | 38 | 45 | 0.219 | 0.76 | 0.47–1.20 |
ITPR1
| Neighbouring genes | – | – | – | – | – | 17 | 20 | 0.507 | 0.77 | 0.37–1.55 |
MKL1
| GWAS proposed | – | – | – | – | – | 26 | 19 | 0.547 | 1.24 | 0.66–2.40 |
CHST9
| GWAS proposed | – | – | – | – | – | 7 | 9 | 0.617 | 0.70 | 0.22–2.13 |
PEX14
| GWAS proposed | – | – | – | – | – | 9 | 6 | 0.613 | 1.36 | 0.43–4.66 |
PAX9
| GWAS proposed | – | – | – | – | – | 3 | 7 | 0.207 | 0.39 | 0.06–1.70 |
PTHLH
| GWAS proposed | – | – | – | – | – | 3 | 1 | 0.626 | 2.72 | 0.22–142.85 |
CDCA7
| GWAS proposed | – | – | – | – | – | 5 | 3 | 0.729 | 1.51 | 0.29–9.76 |
MAP3K1
| GWAS proposed | – | – | – | – | – | 20 | 11 | 0.206 | 1.66 | 0.75–3.85 |
RANBP9
| GWAS proposed | – | – | – | – | – | 10 | 5 | 0.309 | 1.82 | 0.56–6.80 |
DNAJC1
| GWAS proposed | – | – | – | – | – | 8 | 9 | 0.808 | 0.80 | 0.27–2.36 |
TOX3
| GWAS proposed | – | – | – | – | – | 7 | 7 | 1 | 0.90 | 0.27–3.03 |
EPB41L5
| Neighbouring genes | – | – | – | – | – | 8 | 8 | 1 | 0.90 | 0.29–2.78 |
ESR1
| GWAS proposed | – | – | – | – | – | 3 | 6 | 0.323 | 0.45 | 0.07–2.12 |
MDM4
| GWAS proposed | – | – | – | – | – | 7 | 3 | 0.349 | 2.12 | 0.48–12.73 |
CDYL2
| GWAS proposed | – | – | – | – | – | 11 | 5 | 0.217 | 2 | 0.64–7.37 |
TNP1
| Neighbouring genes | – | – | – | – | – | 0 | 2 | 0.226 | 0 | 0–4.82 |
BABAM1
| Neighbouring genes | – | – | – | – | – | 4 | 3 | 1 | 1.21 | 0.20–8.27 |
TGFBR2
| GWAS proposed | – | – | – | – | – | 4 | 3 | 1 | 1.21 | 0.20–8.27 |
ELL
| GWAS proposed | – | – | – | – | – | 9 | 5 | 0.430 | 1.63 | 0.49–6.23 |
NF2
| Neighbouring genes | – | – | – | – | – | 12 | 5 | 0.150 | 2.19 | 0.71–7.95 |
KCNN4
| Neighbouring genes | – | – | – | – | – | 8 | 4 | 0.393 | 1.82 | 0.49–8.27 |
DLX2
| Neighbouring genes | – | – | – | – | – | 7 | 4 | 0.553 | 1.59 | 0.40–7.42 |
KAT5
| Neighbouring genes | – | – | – | – | – | 3 | 2 | 1 | 1.36 | 0.16–16.29 |
COX11
| GWAS proposed | – | – | – | – | – | 2 | 1 | 1 | 1.81 | 0.09–106.93 |
EBF1
| GWAS proposed | – | – | – | – | – | 2 | 3 | 0.673 | 0.60 | 0.05–5.27 |
RAD23B
| Neighbouring genes | – | – | – | – | – | 0 | 1 | 0.475 | 0 | 0–35.30 |
GWAS proposed genes | – | 17 | 4 | 0.008 | 3.89 | 1.26–15.95 | 287 | 251 | 0.679b | 1.05 | 0.86–1.28 |
Neighbouring genes | – | 9 | 9 | 1 | 0.90 | 0.32–2.58 | 168 | 138 | 0.392b | 1.12 | 0.87–1.44 |
Total | – | 26 | 13 | 0.077 | 1.83 | 0.90–3.90 | 406 | 353 | 0.512b | 1.07 | 0.89–1.28 |
Missense variants
Rare missense variants (MAF ≤ 0.001) | Number of carriers | Number of total subjects | p Valuea | OR | 95% CI | ||
---|---|---|---|---|---|---|---|
Cases | Control participants | Cases | Control participants | ||||
All | 406 | 353 | 1043 | 944 | 0.512 | 1.07 | 0.89–1.28 |
Condel deleterious | 174 | 136 | 1043 | 944 | 0.182 | 1.19 | 0.93–1.53 |
PolyPhen-2 Probably/possibly deleterious | 198 | 164 | 1043 | 944 | 0.384 | 1.11 | 0.88–1.41 |
CADD score ≥ 15 | 225 | 173 | 1043 | 944 | 0.08 | 1.23 | 0.98–1.54 |
SIFT deleterious | 171 | 131 | 1043 | 944 | 0.134 | 1.22 | 0.94–1.57 |
REVEL score ≥ 0.5 | 88 | 63 | 1043 | 944 | 0.163 | 1.29 | 0.91–1.83 |
Predicted deleterious by all | 58 | 39 | 1043 | 944 | 0.170 | 1.37 | 0.89–2.13 |