Distinguishing true from false positives in genomic studies: p-values
Linda Broer1*, Christina M. Lill2,3*, Maaike Schuur4*, Najaf Amin1,Johannes T. Roehr2, Lars Bertram2, John P.A. Ioannidis5,6, Cornelia M. van Duijn1
1 Department of Epidemiology, ErasmusUniversityMedicalCenterRotterdam, The Netherlands.
2Neuropsychiatric Genetics Group, Dept. of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
3Dept. of Neurology, UniversityMedicalCenter of the Johannes Gutenberg-University, Mainz, Germany
4 Department of Neurology, ErasmusUniversityMedicalCenterRotterdam, The Netherlands.
5 Stanford Prevention Research Center, Department of Medicine and Department of Health Research and Policy, Stanford University School of Medicine, and Department of Statistics, Stanford University School of Humanities and Sciences, Stanford CA, USA.
6 Department of Hygiene and Epidemiology, University of IoanninaSchool of Medicine, Ioannina, Greece.
* These authors are shared first author
Corresponding author:
Cornelia M van Duijn, PhD, Department of Epidemiology, Erasmus University Medical Center Rotterdam, PO Box 2040, 3000 CA, Rotterdam, The Netherlands. Tel: +31 10 7043362; Fax: +31 10 7044657; E-mail:
Supplementary Tables
Supplementary table 1:AlzGene ‘top list’ at different time-points.
Grade: based on Venice criteria [3]. OR: odds ratio, Regr: modified regression test to assess positive publication bias, HWE: deviations from Hardy-Weinberg Equilibrium, F: loss of significance after exclusion of first study, Excess: evidence for excess of significance. n.a.: Venice grading not applicable (see methods for details)
ST1A: top list of 2005
Gene / Polymorphism / Ethnicity / OR / p-value / N minor(grade) / I2
(grade) / Bias
(grade) / Overall
grade
APOE / APOE_e2/3/4 / All / 3.69 / 9.27*10-120 / 4167 (A) / n.a. / n.a. / A
TF / rs1049296 / All / 1.26 / 0.002 / 2026 (A) / 21 (A) / (A) / A
SOAT1 / rs1044925 / All / 1.31 / 0.002 / 1034 (A) / 0 (A) / (A) / A
ACE / rs1800764 / All / 0.79 / 0.002 / 1371 (A) / 0 (A) / (A) / A
CST3 / rs1064039 / All / 1.16 / 0.022 / 1313 (A) / 0 (A) / (A) / A
CHRNB2 / rs4845378 / All / 0.67 / 0.007 / 227 (B) / 0 (A) / (A) / B
PSEN1 / rs165932 / All / 0.93 / 0.008 / 9241 (A) / 5 (A) / Low OR (C) / C
BDNF / rs6265 / Asian / 0.85 / 0.018 / 1647 (A) / 0 (A) / Regr (C) / C
ESR1 / rs9340799 / All / 1.20 / 0.029 / 6005 (A) / 56 (C) / F (C) / C
PRNP / rs1799990 / All / 0.90 / 0.043 / 2703 (A) / 4 (A) / Low OR, F (C) / C
OLR1 / rs1050283 / All / 0.88 / 0.047 / 5516 (A) / 59 (C) / Low OR (C) / C
IDE / rs2251101 / All / 0.89 / 0.048 / 2187 (A) / 22 (A) / Low OR, F, HWE (C) / C
ST1B: top list of 2006
Gene / Polymorphism / Ethnicity / OR / p-value / N minor(grade) / I2
(grade) / Bias
(grade) / Overall
grade
APOE / APOE_e2/3/4 / All / 3.69 / 9.27*10-120 / 4167 (A) / n.a. / n.a. / A
DAPK1 / rs4878104 / All / 0.87 / 0.002 / 3141 (A) / 0 (A) / (A) / A
SOAT1 / rs1044925 / All / 1.31 / 0.002 / 1034 (A) / 0 (A) / (A) / A
ACE / rs1800764 / Caucasian / 0.79 / 0.002 / 1371 (A) / 0 (A) / (A) / A
TF / rs1049296 / All / 1.22 / 0.003 / 2256 (A) / 19 (A) / (A) / A
IL1B / rs1143634 / Caucasian / 1.18 / 0.013 / 1206 (A) / 0 (A) / (A) / A
PON1 / rs662 / All / 0.86 / 0.018 / 2226 (A) / 0 (A) / (A) / A
CST3 / rs1064039 / All / 1.16 / 0.022 / 1313 (A) / 0 (A) / (A) / A
MAPT/STH / rs1467967 / All / 0.87 / 0.050 / 1176 (A) / 0 (A) / (A) / A
hCG2039140 / rs1903908 / All / 1.23 / 0.007 / 768 (B) / 0 (A) / (A) / B
CHRNB2 / rs4845378 / All / 0.67 / 0.007 / 227 (B) / 0 (A) / (A) / B
SORCS1 / rs600879 / All / 1.24 / 0.017 / 567 (B) / 0 (A) / (A) / B
PSEN1 / rs165932 / All / 0.91 / 0.011 / 10002 (A) / 47 (B) / Low OR, Regr (C) / C
CH25H / rs13500 / All / 1.44 / 0.014 / 729 (B) / 65 (C) / Regr (C) / C
LOC439999 / rs498055 / All / 1.15 / 0.016 / 5282 (A) / 49 (B) / HWE (C) / C
PRNP / rs1799990 / Caucasian / 0.89 / 0.020 / 2872 (A) / 17 (A) / Low OR, F, HWE (C) / C
CTSD / rs17571 / Caucasian / 1.22 / 0.034 / 1192 (A) / 50 (B) / F, Excess (C) / C
OLR1 / rs1050283 / All / 0.88 / 0.047 / 5516 (A) / 59 (C) / Low OR (C) / C
ST1C: top list of 2007
Gene / Polymorphism / Ethnicity / OR / p-value / N minor(grade) / I2
(grade) / Bias
(grade) / Overall
grade
APOE / APOE_e2/3/4 / All / 3.69 / 9.27*10-120 / 4167 (A) / n.a. / n.a. / A
SORL1 / rs2070045 / Caucasian / 1.21 / 1.01*10-4 / 2830 (A) / 16 (A) / (A) / A
GALP / rs3745833 / All / 1.21 / 1.20*10-4 / 2699 (A) / 0 (A) / (A) / A
GWA_14q32.13 / rs11622883 / All / 0.84 / 3.38*10-4 / 3174 (A) / 0 (A) / (A) / A
TNK1 / rs1554948 / All / 0.84 / 0.001 / 3538 (A) / 12 (A) / (A) / A
PCK1 / rs8192708 / All / 1.28 / 0.001 / 1008 (A) / 12 (A) / (A) / A
DAPK1 / rs4878104 / All / 0.87 / 0.002 / 3141 (A) / 0 (A) / (A) / A
TFAM / rs2306604 / All / 0.78 / 0.002 / 1174 (A) / 0 (A) / (A) / A
ACE / rs1800764 / Caucasian / 0.79 / 0.002 / 1371 (A) / 0 (A) / (A) / A
CST3 / rs1064039 / All / 1.18 / 0.007 / 1461 (A) / 0 (A) / (A) / A
LOC651924 / rs6907175 / All / 0.86 / 0.009 / 2563 (A) / 10 (A) / (A) / A
IL1B / rs1143634 / Caucasian / 1.18 / 0.013 / 1206 (A) / 0 (A) / (A) / A
LMNA / rs505058 / All / 1.35 / 0.001 / 493 (B) / 0 (A) / (A) / B
PGBD1 / rs3800324 / All / 1.42 / 0.003 / 302 (B) / 0 (A) / (A) / B
hCG2039140 / rs1903908 / All / 1.23 / 0.007 / 768 (B) / 0 (A) / (A) / B
CHRNB2 / rs4845378 / All / 0.67 / 0.007 / 227 (B) / 0 (A) / (A) / B
SORCS1 / rs600879 / All / 1.24 / 0.017 / 567 (B) / 0 (A) / (A) / B
TF / rs1049296 / All / 1.18 / 0.012 / 2747 (A) / 30 (B) / Regr (C) / C
CH25H / rs13500 / All / 1.44 / 0.014 / 729 (B) / 65 (C) / Regr (C) / C
LOC439999 / rs498055 / All / 1.15 / 0.016 / 5282 (A) / 49 (B) / HWE (C) / C
PRNP / rs1799990 / All / 0.90 / 0.016 / 3001 (A) / 1 (A) / Low OR, F (C) / C
PSEN1 / rs165932 / All / 0.92 / 0.028 / 10163 (A) / 50 (B) / Low OR, F, Regr (C) / C
MTHFR / rs1801133 / All / 1.12 / 0.030 / 5317 (A) / 27 (B) / Low OR (C) / C
CTSD / rs17571 / Caucasian / 1.22 / 0.034 / 1192 (A) / 50 (B) / F, Excess (C) / C
BDNF / rs6265 / Caucasian / 1.09 / 0.039 / 3260 (A) / 0 (A) / Low OR (C) / C
MAPT/STH / rs1467967 / All / 0.88 / 0.042 / 1679 (A) / 0 (A) / Low OR, F (C) / C
MYH13 / rs2074877 / All / 1.12 / 0.043 / 2735 (A) / 24 (A) / Low OR (C) / C
OLR1 / rs1050283 / All / 0.88 / 0.047 / 5516 (A) / 59 (C) / Low OR (C) / C
ST1D: top list of 2008
Gene / Polymorphism / Ethnicity / OR / p-value / N minor(grade) / I2
(grade) / Bias
(grade) / Overall
grade
APOE / APOE_e2/3/4 / All / 3.69 / 9.27*10-120 / 4167 (A) / n.a. / n.a. / A
GWA_14q32.13 / rs11622883 / All / 0.84 / 3.38*10-4 / 3174 (A) / 0 (A) / (A) / A
TNK1 / rs1554948 / All / 0.84 / 0.001 / 3538 (A) / 12 (A) / (A) / A
ACE / rs1800764 / Caucasian / 0.79 / 0.002 / 1371 (A) / 0 (A) / (A) / A
TFAM / rs2306604 / All / 0.82 / 0.003 / 1604 (A) / 0 (A) / (A) / A
IL1B / rs1143634 / Caucasian / 1.18 / 0.013 / 1206 (A) / 0 (A) / (A) / A
CST3 / rs1064039 / Caucasian / 1.16 / 0.043 / 1203 (A) / 13 (A) / (A) / A
GAB2 / rs4945261 / Caucasian / 0.74 / 1.87*10-5 / 2779 (A) / 34 (B) / (A) / B
OTC / rs5963409 / All / 1.21 / 0.001 / 2541 (A) / 28 (B) / (A) / B
hCG2039140 / rs1903908 / All / 1.23 / 0.007 / 768 (B) / 0 (A) / (A) / B
SORL1 / rs12285364 / Caucasian / 1.26 / 0.007 / 680 (B) / 7 (A) / (A) / B
CHRNB2 / rs4845378 / All / 0.67 / 0.007 / 227 (B) / 0 (A) / (A) / B
SORCS1 / rs600879 / All / 1.24 / 0.017 / 567 (B) / 0 (A) / (A) / B
TNF / rs4647198 / Asian / 1.37 / 0.019 / 301 (B) / 0 (A) / (A) / B
DAPK1 / rs4878104 / All / 0.88 / 0.002 / 4219 (A) / 0 (A) / Low OR, Regr (C) / C
CALHM1 / rs2986017 / All / 1.30 / 0.002 / 2455 (A) / 59 (C) / (A) / C
LOC651924 / rs6907175 / All / 0.89 / 0.005 / 4484 (A) / 3 (A) / Low OR (C) / C
TF / rs1049296 / All / 1.17 / 0.006 / 3173 (A) / 24 (A) / Regr (C) / C
NEDD9 / rs760678 / All / 0.89 / 0.012 / 5336 (A) / 39 (B) / Low OR, F, Regr (C) / C
MTHFR / rs1801133 / All / 1.12 / 0.012 / 6328 (A) / 21 (A) / Low OR (C) / C
BDNF / rs6265 / Caucasian / 1.09 / 0.013 / 3964 (A) / 0 (A) / Low OR (C) / C
CH25H / rs13500 / All / 1.44 / 0.014 / 729 (B) / 65 (C) / Regr (C) / C
LOC439999 / rs498055 / All / 1.15 / 0.016 / 5282 (A) / 49 (B) / HWE (C) / C
PGBD1 / rs3800324 / All / 1.26 / 0.017 / 469 (B) / 0 (A) / Regr (C) / C
PSEN1 / rs165932 / All / 0.92 / 0.029 / 13145 (A) / 53 (C) / Low OR, F, HWE (C) / C
ENTPD7 / rs911541 / All / 1.10 / 0.034 / 2241 (A) / 1 (A) / Low OR, F (C) / C
MAPT/STH / rs2471738 / All / 1.25 / 0.037 / 1250 (A) / 58 (C) / F, Regr (C) / C
PRNP / rs1799990 / All / 0.91 / 0.040 / 3386 (A) / 2 (A) / Low OR, F, HWE (C) / C
IL1A / rs1800587 / All / 1.09 / 0.043 / 5321 (A) / 29 (B) / Low OR, F (C) / C
OLR1 / rs1050283 / All / 0.88 / 0.047 / 5516 (A) / 59 (C) / Low OR (C) / C
GAPDHS / rs4806173 / All / 0.87 / 0.048 / 2623 (A) / 51 (C) / (A) / C
ST1E: top list of 2009
Gene / Polymorphism / Ethnicity / OR / p-value / N minor(grade) / I2
(grade) / Bias
(grade) / Overall
grade
APOE / APOE_e2/3/4 / All / 3.69 / 9.27*10-120 / 4167 (A) / n.a. / n.a. / A
PVRL2 / rs6859 / All / 1.50 / 2.44*10-28 / 15728 (A) / n.a. / n.a. / A
CLU / rs11136000 / All / 0.86 / 3.06*10-16 / 20616 (A) / n.a. / n.a. / A
PICALM / rs541458 / All / 0.87 / 3.49*10-9 / 12508 (A) / n.a. / n.a. / A
GWA_14q32.13 / rs11622883 / All / 0.84 / 3.38*10-4 / 3174 (A) / 0 (A) / (A) / A
TNK1 / rs1554948 / All / 0.84 / 0.001 / 3538 (A) / 12 (A) / (A) / A
ACE / rs1800764 / Caucasian / 0.79 / 0.002 / 1371 (A) / 0 (A) / (A) / A
IL8 / rs4073 / All / 1.27 / 0.004 / 1157 (A) / 0 (A) / (A) / A
LDLR / rs5930 / All / 0.85 / 0.039 / 1228 (A) / 1 (A) / (A) / A
CST3 / rs1064039 / Caucasian / 1.16 / 0.043 / 1203 (A) / 13 (A) / (A) / A
OTC / rs5963409 / All / 1.21 / 0.001 / 2541 (A) / 28 (B) / (A) / B
hCG2039140 / rs1903908 / All / 1.23 / 0.007 / 768 (B) / 0 (A) / (A) / B
CHRNB2 / rs4845378 / All / 0.67 / 0.007 / 227 (B) / 0 (A) / (A) / B
SORCS1 / rs600879 / All / 1.24 / 0.017 / 567 (B) / 0 (A) / (A) / B
TNF / rs4647198 / Asian / 1.37 / 0.019 / 301 (B) / 0 (A) / (A) / B
CCR2 / rs1799864 / Caucasian / 0.73 / 0.024 / 308 (B) / 0 (A) / (A) / B
BCAM / rs1871045 / All / 0.90 / 6.35*10-5 / 10583 (A) / 0 (A) / Low OR (C) / C
PCDH11X / rs5984894 / All / 0.85 / 1.50*10-4 / 11801 (A) / 37 (B) / Regr (C) / C
CR1 / rs6656401 / All / 1.19 / 1.65*10-4 / 6059 (A) / 52 (C) / (A) / C
SORL1 / rs2282649 / Asian / 1.30 / 1.74*10-4 / 1598 (A) / 0 (A) / Excess (C) / C
DAPK1 / rs4878104 / All / 0.88 / 0.002 / 4219 (A) / 0 (A) / Low OR, Regr (C) / C
GAB2 / rs2373115 / All / 0.85 / 0.002 / 6275 (A) / 60 (C) / Regr (C) / C
TF / rs1049296 / All / 1.18 / 0.002 / 3326 (A) / 22 (A) / Regr (C) / C
MTHFR / rs1801133 / All / 1.13 / 0.003 / 7064 (A) / 22 (A) / Low OR (C) / C
LOC651924 / rs6907175 / All / 0.89 / 0.005 / 4484 (A) / 3 (A) / Low OR (C) / C
ADAM10 / rs17269348 / All / 1.15 / 0.010 / 2679 (A) / 23 (A) / Low OR (C) / C
NEDD9 / rs760678 / All / 0.89 / 0.012 / 5336 (A) / 39 (B) / Low OR, F, Regr (C) / C
CH25H / rs13500 / All / 1.44 / 0.014 / 729 (B) / 65 (C) / Regr (C) / C
LOC439999 / rs498055 / All / 1.15 / 0.016 / 5282 (A) / 49 (B) / HWE (C) / C
CALHM1 / rs2986017 / Caucasian / 1.18 / 0.016 / 4523 (A) / 68 (C) / F (C) / C
GRN / rs5848 / All / 1.13 / 0.017 / 2373 (A) / 0 (A) / Low OR (C) / C
IL33 / rs7044343 / All / 0.85 / 0.021 / 7122 (A) / 57 (C) / (A) / C
IL1B / rs1143634 / Caucasian / 1.16 / 0.021 / 1450 (A) / 0 (A) / HWE (C) / C
PGBD1 / rs3800324 / All / 1.21 / 0.028 / 550 (B) / 0 (A) / Regr (C) / C
THRA / rs939348 / All / 1.10 / 0.030 / 3248 (A) / 0 (A) / Low OR, Regr (C) / C
ENTPD7 / rs911541 / All / 1.10 / 0.034 / 2241 (A) / 1 (A) / Low OR, F (C) / C
TFAM / rs2306604 / All / 0.86 / 0.036 / 1983 (A) / 17 (A) / F (C) / C
IL1A / rs1800587 / Caucasian / 1.09 / 0.039 / 4985 (A) / 20 (A) / Low OR, F (C) / C
ECE1 / rs213045 / All / 0.86 / 0.044 / 1952 (A) / 42 (B) / F (C) / C
PRNP / rs1799990 / Caucasian / 0.92 / 0.045 / 4089 (A) / 6 (A) / Low OR, F, HWE (C) / C
OLR1 / rs1050283 / All / 0.88 / 0.047 / 5516 (A) / 59 (C) / Low OR (C) / C
GAPDHS / rs4806173 / All / 0.87 / 0.048 / 2623 (A) / 51 (C) / (A) / C
ST1F: top list of 2010
Gene / Polymorphism / Ethnicity / OR / p-value / N minor(grade) / I2
(grade) / Bias
(grade) / Overall
grade
APOE / APOE_e2/3/4 / All / 3.69 / 9.27*10-120 / 4167 (A) / n.a. / n.a. / A
PVRL2 / rs6859 / All / 1.50 / 2.44*10-28 / 15728 (A) / n.a. / n.a. / A
CLU / rs11136000 / Caucasian / 0.88 / 4.72*10-23 / 54057 (A) / n.a. / n.a. / A
PICALM / rs3851179 / Caucasian / 0.88 / 5.20*10-18 / 44659 (A) / n.a. / n.a. / A
EXOC3L2 / rs597668 / All / 1.17 / 2.04*10-10 / 13519 (A) / n.a. / n.a. / A
GWA_14q32.13 / rs11622883 / All / 0.84 / 3.38*10-4 / 3174 (A) / 0 (A) / (A) / A
TNK1 / rs1554948 / All / 0.84 / 0.001 / 3538 (A) / 12 (A) / (A) / A
IL8 / rs4073 / All / 1.27 / 0.004 / 1157 (A) / 0 (A) / (A) / A
IDE / rs7910977 / All / 0.84 / 0.015 / 1152 (A) / 11 (A) / (A) / A
LDLR / rs5930 / All / 0.85 / 0.039 / 1228 (A) / 1 (A) / (A) / A
CST3 / rs1064039 / Caucasian / 1.16 / 0.043 / 1203 (A) / 13 (A) / (A) / A
CR1 / rs6656401 / Caucasian / 1.18 / 2.56*10-5 / 7859 (A) / 49 (B) / (A) / B
OTC / rs5963409 / All / 1.21 / 0.001 / 2541 (A) / 28 (B) / (A) / B
hCG2039140 / rs1903908 / All / 1.23 / 0.007 / 768 (B) / 0 (A) / (A) / B
CHRNB2 / rs4845378 / All / 0.67 / 0.007 / 227 (B) / 0 (A) / (A) / B
SORCS1 / rs600879 / All / 1.24 / 0.017 / 567 (B) / 0 (A) / (A) / B
TNF / rs4647198 / Asian / 1.37 / 0.019 / 301 (B) / 0 (A) / (A) / B
CCR2 / rs1799864 / Caucasian / 0.73 / 0.024 / 308 (B) / 0 (A) / (A) / B
BCAM / rs1871045 / All / 0.90 / 6.35*10-5 / 10583 (A) / 0 (A) / Low OR (C) / C
PCDH11X / rs5984894 / All / 0.85 / 7.17*10-5 / 11993 (A) / 36 (B) / F, Regr (C) / C
SORL1 / rs2282649 / Asian / 1.30 / 1.74*10-4 / 1598 (A) / 0 (A) / Excess (C) / C
ACE / rs1800764 / Caucasian / 0.84 / 3.12*10-4 / 3496 (A) / 0 (A) / F (C) / C
DAPK1 / rs4878104 / All / 0.88 / 0.002 / 4219 (A) / 0 (A) / Low OR, Regr (C) / C
GAB2 / rs2373115 / All / 0.85 / 0.002 / 6275 (A) / 60 (C) / Regr (C) / C
TF / rs1049296 / All / 1.18 / 0.002 / 3326 (A) / 22 (A) / Regr (C) / C
MTHFR / rs1801133 / All / 1.13 / 0.003 / 7064 (A) / 22 (A) / Low OR (C) / C
LOC651924 / rs6907175 / All / 0.89 / 0.005 / 4484 (A) / 3 (A) / Low OR (C) / C
ADAM10 / rs17269348 / All / 1.15 / 0.010 / 2679 (A) / 23 (A) / Low OR (C) / C
NEDD9 / rs760678 / All / 0.89 / 0.012 / 5336 (A) / 39 (B) / Low OR, F, Regr (C) / C
CH25H / rs13500 / All / 1.44 / 0.014 / 729 (B) / 65 (C) / Regr (C) / C
LOC439999 / rs498055 / All / 1.15 / 0.016 / 5282 (A) / 49 (B) / HWE (C) / C
GRN / rs5848 / All / 1.13 / 0.017 / 2373 (A) / 0 (A) / Low OR (C) / C
IL33 / rs7044343 / All / 0.85 / 0.021 / 7122 (A) / 57 (C) / (A) / C
IL1B / rs1143634 / Caucasian / 1.16 / 0.021 / 1450 (A) / 0 (A) / HWE (C) / C
PGBD1 / rs3800324 / All / 1.21 / 0.028 / 550 (B) / 0 (A) / Regr (C) / C
THRA / rs939348 / All / 1.10 / 0.030 / 3248 (A) / 0 (A) / Low OR, Regr (C) / C
CALHM1 / rs2986017 / Caucasian / 1.12 / 0.030 / 7185 (A) / 66 (C) / Low OR, F (C) / C
ENTPD7 / rs911541 / All / 1.10 / 0.034 / 2241 (A) / 1 (A) / Low OR, F (C) / C
TFAM / rs2306604 / All / 0.86 / 0.036 / 1983 (A) / 17 (A) / F (C) / C
IL1A / rs1800587 / Caucasian / 1.09 / 0.039 / 4985 (A) / 20 (A) / Low OR, F (C) / C
ECE1 / rs213045 / All / 0.86 / 0.044 / 1952 (A) / 42 (B) / F (C) / C
PRNP / rs1799990 / Caucasian / 0.92 / 0.045 / 4089 (A) / 6 (A) / Low OR, F, HWE (C) / C
GAPDHS / rs4806173 / All / 0.87 / 0.048 / 2623 (A) / 51 (C) / (A) / C