Background
Methods
Study sample
Phenotype definition
Exam cycle | |||||
---|---|---|---|---|---|
Phenotypic Trait (Abbreviated Variable Name) | Number of traits | N | Original Cohort (Exam 26) | Offspring Cohort (Exam 7) | Covariates Used to Create Multivariable-Adjusted Residuals |
Volumetric Brain MRI*
| |||||
Total Cerebral Brain Volume (ATCBV) | 1 | 705 | Original Cohort & Offspring data are pooled | Age, age-squared, sex, current smoking status, diabetes, systolic blood pressure, anti-hypertensive drugs, atrial fibrillation, EKG-LVH at Offspring examination 7 and Original cohort 26; data from sex-specific regressions pooled. | |
Frontal Brain volume (AFBV) | 1 | 705 | |||
Parietal Brain Volume (APBV) | 1 | 705 | |||
Occipital Brain Volume (AOBV) | 1 | 705 | |||
Temporal Brain volume (ATBV) | 1 | 705 | |||
Hippocampal Volume (AHPV) | 1 | 327 | |||
Lateral Ventricular Volume (ALVV)† | 1 | 705 | |||
Temporal Horn Volume (LTHBV)† | 1 | 705 | |||
White Matter Hyperintensity Volume (BMRIZLWMHVMV) [Age-, sex-specific Z-score of log-normalized white matter hyperintensity volume] | 1 | 705 | Current smoking status, diabetes, systolic blood pressure, anti-hypertensive drugs, atrial fibrillation, EKG-LVH at Offspring examination 7 and Original cohort 26; data from sex-specific regressions pooled. | ||
Cognitive Test Performance
| |||||
Factor 1:Verbal Memory (F1) | 1 | 694 | Original cohort and Offspring data are pooled | Birth cohort by decade, education, Framingham Stroke Risk Profile score, plasma homocysteine concentrations (at the 20th Original cohort and the 6th Offspring examinations), apolipoprotein E genotype (ε4 +ve/-ve); data from sex-specific regressions were pooled. | |
Factor 2:Visual Memory and Organization (F2) | 1 | 694 | |||
Factor 3: Measure of attention and executive function-Trails A and B (F3) | 1 | 694 | |||
Boston Naming Test (Nam) | 1 | 694 | |||
Similarities (Sim) | 1 | 694 | |||
Wide-Range Achievement Test (WRAT) | 1 | 694 |
Volumetric brain MRI
Cognitive measures
Genotyping
Statistical analysis
Presentation of results
2, section a: GEE, Top 25 p-values | ||||||
---|---|---|---|---|---|---|
Phenotype | SNP | Chromosome | Physical location | GEE p-value | FBAT p-value | Gene Region (within 60 kb) |
ATCBV | rs1970546 | 20 | 59287333 | 4.0 × 10-8 | 0.005 |
CDH4
|
F3 | rs2179965* | 1 | 88514033 | 1.1 × 10-6 | 0.013 | |
Nam | rs1155865 | 4 | 67562623 | 1.6 × 10-6 | 0.554 | |
F3 | rs2832077 | 21 | 29062892 | 1.8 × 10-6 | 0.007 | |
F2 | rs2352904 | 14 | 48442551 | 2.1 × 10-6 | 0.012 | |
F2 | rs6914079* | 6 | 14704344 | 2.2 × 10-6 | 0.018 | |
F2 | rs9325032 | 5 | 146395409 | 2.8 × 10-6 | 0.008 | |
ALLV | rs2847476 | 11 | 113696226 | 3.0 × 10-6 | 0.001 |
NNMT
|
Sim | rs3891355 | 12 | 105453162 | 3.2 × 10-6 | 0.089 | POLR3B, RFX4 |
ATBV | rs5028798 | 11 | 34562011 | 3.3 × 10-6 | 0.394 |
EHF
|
Nam | rs530965 | 11 | 78742749 | 3.5 × 10-6 | 0.119 | |
Nam | rs9303401 | 17 | 54202944 | 4.9 × 10-6 | 0.099 |
PPM1E
|
AFBV | rs952700 | 11 | 99090946 | 5.7 × 10-6 | 0.003 |
CNTN5
|
F3 | rs1031381 | 11 | 133593892 | 6.0 × 10-6 | 0.075 |
NCAPD3
|
F2 | rs10489896* | 1 | 230890353 | 6.2 × 10-6 | 0.109 |
TARBP1
|
WRAT | rs9300212 | 12 | 33592433 | 8.2 × 10-6 | 0.002 | |
Nam | rs1831521 | 9 | 90488911 | 8.4 × 10-6 | 0.002 |
DIRAS2
|
F3 | rs934299 | 2 | 137172672 | 9.0 × 10-6 | 0.318 | |
ALTHBV | rs360929 | 4 | 153265305 | 9.1 × 10-6 | 0.055 | |
F2 | rs2893363 | 7 | 29952294 | 9.6 × 10-6 | 0.812 |
C7orf41
|
WRAT | rs10502991 | 18 | 50243287 | 1.0 × 10-5 | 0.001 | |
APBV | rs2769965 | 9 | 79048598 | 1.1 × 10-5 | 0.012 | |
APBV | rs719435 | 7 | 31324796 | 1.1 × 10-5 | 0.188 |
CCDC129
|
F1 | rs9292769 | 5 | 40433668 | 1.1 × 10-5 | 0.163 | |
Nam | rs10506718 | 12 | 75377929 | 1.1 × 10-5 | 0.402 | |
2, section b: FBAT, Top 25 p-values
| ||||||
Trait
|
SNP
|
Chromosome
|
Physical location
|
GEE p-value
|
FBAT p-value
|
Gene Region(s) (within 60 kb)
|
ALLV | rs7124781 | 11 | 42513374 | 0.008 | 2.0 × 10-7 | |
Sim | rs1131497 | 11 | 121007955 | 0.008 | 3.2 × 10-6 |
SORL1
|
WRAT | rs10506065 | 12 | 30342307 | 0.050 | 5.0 × 10-6 | |
AFBV | rs3852286 | 7 | 140126618 | 0.145 | 6.5 × 10-6 |
BRAF and MRPS33
|
WRAT | rs4529807 | 10 | 22358107 | 0.013 | 1.1 × 10-5 |
DNAJC1
|
F3 | rs847342 | 14 | 71805791 | 0.441 | 1.3 × 10-5 |
RGS6
|
AFBV | rs719775 | 3 | 64366493 | 0.001 | 1.8 × 10-5 | |
Sim | rs936111 | 15 | 99376659 | 0.014 | 2.1 × 10-5 |
LRRK1
|
ATBV | rs2143881 | 6 | 50960846 | 0.077 | 2.1 × 10-5 |
TFAP2B
|
AHPV | rs9293140 | 5 | 24643203 | 0.092 | 2.1 × 10-5 |
CDH10
|
AFBV | rs9288446* | 2 | 212907533 | 0.001 | 2.3 × 10-5 |
ERBB4
|
APBV | rs1472962 | 4 | 95949555 | 0.004 | 3.1 × 10-5 |
PDLIM5
|
ATBV | rs2793772 | 13 | 99029574 | 0.047 | 3.3 × 10-5 |
CLYBL
|
F2 | rs1333583 | 13 | 82037151 | 0.031 | 3.4 × 10-5 | |
ATBV | rs10497352 | 2 | 170781278 | 0.005 | 3.6 × 10-5 |
ZNF650
|
F1 | rs497836 | 13 | 93605509 | 0.020 | 3.8 × 10-5 |
GPC6
|
APBV | rs6459928 | 7 | 158428045 | 0.271 | 4.0 × 10-5 |
VIPR2
|
AHPV | rs1963442 | 3 | 75872661 | 0.046 | 4.3 × 10-5 |
ZNF717
|
APBV | rs10503238 | 8 | 4027465 | 0.002 | 4.4 × 10-5 | |
F2 | rs2861215 | 2 | 77958447 | 0.006 | 4.7 × 10-5 | |
Nam | rs9311168 | 3 | 37952421 | 0.067 | 4.9 × 10-5 |
CTDSPL
|
F2 | rs2029395 | 2 | 1.8 × 10-8 | 0.027 | 4.9 × 10-5 | TTN, FLJ39502 |
ATCBV | rs10510717 | 3 | 41307494 | 0.005 | 5.0 × 10-5 |
CTNNB1
|
ATBV | rs1433527 | 2 | 1.8 × 10-8 | 0.028 | 5.1 × 10-5 |
DDX18
|
2, section c: Linkage Peaks with LOD scores ≥ 2.0.
| ||||||
Trait
|
SNP closest to linkage peak
|
Chromosome
|
Physical location
|
1.5 – LOD support interval start
|
1.5 – LOD support interval end
|
LOD score
|
WATBV† | rs1547275 | 9 | 79548023 | 76128637 | 86702472 | 2.81 |
WF3† | rs2975420 | 8 | 19534278 | 12651557 | 22836499 | 2.20 |
WNam† | rs2765241 | 1 | 62439617 | 59085658 | 67006164 | 2.95 |
WNam† | rs293966 | 11 | 26536069 | 21237681 | 33363547 | 2.14 |
WWRAT† | rs10512187 | 9 | 87400439 | 84893406 | 110115339 | 2.04 |
WWRAT† | rs1328822 | 13 | 93605666 | 87815515 | 97536766 | 2.50 |
WWRAT†
|
rs1846090
|
18
|
14573728
|
13423610
|
19583575
|
5.10
|
WWRAT† | rs10518241 | 19 | 3540074 | 1888178 | 6189414 | 2.33 |
BMRIZLWMHVMV
|
rs4426714
|
4
|
5052671
|
105905
|
9505355
|
2.20
|
BMRIZLWMHVMV | rs236535 | 17 | 65788911 | 59677087 | 68475624 | 2.09 |
Gene | Phenotype | SNP | Chr | Physical Position | GEE_Pvalue | FBAT_Pvalue |
---|---|---|---|---|---|---|
NGFB
| AHPV | rs10489531 | 1 | 115495044 | 9.7 × 10-4 | 0.046 |
PRSS25
| ATBV | rs363685 | 2 | 74726491 | 2.5 × 10-4 | |
ATCBV | rs363685 | 2 | 74726491 | 5.7 × 10-5 | ||
GRK4
| F1 | rs2105380 | 4 | 3019934 | 0.276 | 5.8 × 10-4 |
HMGE
| ATBV | rs4689584 | 4 | 7179291 | 0.035 | 1.0 × 10-4 |
APBB2
| F1 | rs10517001 | 4 | 41051593 | 1.4 × 10-4 | 0.009 |
SNCA
| Sim | rs3796661 | 4 | 91044685 | 2.6 × 10-4 | 0.332 |
AHPV | rs2870028 | 4 | 91122391 | 3.2 × 10-4 | 0.180 | |
AHPV | rs7678651 | 4 | 91125549 | 1.3 × 10-4 | 0.102 | |
AHPV | rs10516848 | 4 | 91132390 | 1.6 × 10-4 | 0.115 | |
PDE4D
| WRAT | rs295973 | 5 | 58945866 | 5.3 × 10-4 | 0.060 |
Sim | rs10514882 | 5 | 59170282 | 6.4 × 10-5 | ||
Sim | rs9292216 | 5 | 59187886 | 2.4 × 10-4 | ||
DCDC2
| F3 | rs10484657 | 6 | 24224829 | 0.017 | 9.5 × 10-4 |
ATCBV | rs10484657 | 6 | 24224829 | 6.0 × 10-4 | 0.015 | |
THBS2
| ATBV | rs6937001 | 6 | 169382718 | 6.0 × 10-4 | 0.021 |
GATA4
| WRAT | rs7006733 | 8 | 11645399 | 0.034 | 3.1 × 10-4 |
NRG1
| ATCBV | rs1383893 | 8 | 31844190 | 0.407 | 8.9 × 10-4 |
F2 | rs10503906 | 8 | 32291504 | 0.187 | 4.2 × 10-4 | |
AFBV | rs10503919 | 8 | 32519284 | 1.9 × 10-4 | 0.288 | |
BMRIZLWMH | rs10503926 | 8 | 32660758 | 8.7 × 10-5 | 0.009 | |
VMV | rs10503927 | 8 | 32662772 | 2.0 × 10-4 | 0.002 | |
VLDLR
| ATCBV | rs502309 | 9 | 2562909 | 5.4 × 10-6 | 0.157 |
Nam | rs2168136 | 9 | 2584577 | 1.6 × 10-4 | 0.006 | |
NTRK2
| F1 | rs10512152 | 9 | 84457363 | 7.6 × 10-5 | 0.018 |
AFBV | rs1573219 | 9 | 84617176 | 0.174 | 5.6 × 10-4 | |
AFBV | rs7038866 | 9 | 84617461 | 0.146 | 3.6 × 10-4 | |
TEK | ATBV | rs628873 | 9 | 27162838 | 4.9 × 10-4 | 0.051 |
BACE1
| APBV | rs1261791 | 11 | 116705848 | 0.021 | 3.1 × 10-4 |
SORL1
| Sim | rs1131497 | 11 | 121007955 | 0.008 | 3.2 × 10-6 |
Sim | rs726601 | 11 | 120986617 | 0.046 | 8.2 × 10-4 | |
VWF
| ATCBV | rs216903 | 12 | 5975760 | 0.149 | 9.5 × 10-4 |
A2M
| F3 | rs2889717 | 12 | 9178068 | 9.3 × 10-5 | |
LRRK2
| WRAT | rs2249017 | 12 | 38847487 | 5.5 × 10-4 | 0.061 |
F1 | rs7975693 | 12 | 38874945 | 8.1 × 10-5 | 0.005 | |
AFBV | rs10506151 | 12 | 38957265 | 3.7 × 10-4 | 1.6 × 10-4 | |
ATBV | rs10506151 | 12 | 38957265 | 9.7 × 10-4 | 0.371 | |
CNTN1
| ATBV | rs10506176 | 12 | 39561067 | 8.8 × 10-4 | 0.622 |
LTA4H
| Sim | rs10492226 | 12 | 94906457 | 6.7 × 10-4 | |
IGF1
| ALLV | rs1980236 | 12 | 101270359 | 0.046 | 9.3 × 10-4 |
LTB4R2
| APBV | rs724165 | 14 | 23876069 | 4.5 × 10-4 | 0.162 |
NTRK3
| ALLV | rs10520671 | 15 | 86347520 | 6.2 × 10-5 | 0.062 |
CCL2
| WRAT | rs1024612 | 17 | 29573469 | 0.231 | 7.0 × 10-4 |
PRKCA
| F1 | rs9303511 | 17 | 62158093 | 0.068 | 7.9 × 10-4 |
CST3
| AOBV | rs1158167 | 20 | 23526189 | 6.5 × 10-4 | 0.032 |
PRNP
| APBV | rs2326510 | 20 | 4649211 | 0.000718 | 0.064794 |
BACE2
| F1 | rs2007397 | 21 | 41438062 | 0.030 | 2.2 × 10-4 |
F1 | rs10483073 | 21 | 41499167 | 3.5 × 10-4 | ||
Nam | rs10483073 | 21 | 41499167 | 1.7 × 10-4 |
Results
Selected Phenotype : (p < 0.001) | SNP | Chr | Physical Position | Gene | MRI phenotype showing strongest association with SNP | GEE p-value |
---|---|---|---|---|---|---|
TCBV
| rs646860 | 1 | 60310322 |
C1orf87
| APBV | 6.5 × 10-4 |
TCBV
| rs7763081 | 6 | 53816274 |
LRRC1
| ATCBV | 6.5 × 10-4 |
TCBV
| rs1444644 | 12 | 20457227 |
PDE3A
| ATBV | 8.8 × 10-5 |
TCBV
| rs10505865 | 12 | 20453861 |
PDE3A
| AFBV | 1.4 × 10-4 |
TCBV
| rs1444645 | 12 | 20457264 |
PDE3A
| ATBV | 1.8 × 10-4 |
TCBV
| rs1444629 | 12 | 20454174 |
PDE3A
| ATCBV | 2.7 × 10-4 |
TCBV
| rs303816 | 12 | 50469752 |
SCN8A
| ATCBV | 6.1 × 10-4 |
TCBV
| rs2827980† | 21 | 23524857 | ATCBV | 5.9 × 10-5 | |
TCBV
| rs9297594† | 8 | 120287483 | AFBV | 1.3 × 10-4 | |
TCBV
| rs10512927† | 5 | 50346833 | ATCBV | 8.5 × 10-4 | |
Selected Phenotype : (p < 0.001)
|
SNP
|
Chr
|
Physical Position
|
Gene
|
Phenotype showing strongest association with SNP
|
FBAT p-value
|
TCBV
| rs7740148 | 6 | 35063681 |
ANKS1
| AFBV | 0.003 |
TCBV
| rs6496742 | 15 | 89324040 |
PRC1
| ATCBV | 6.4 × 10-4 |
TCBV
| rs2788646 | 1 | 66518974 |
PDE4B
| ATCBV | 3.3 × 10-4 |
TCBV
| rs10500956† | 11 | 23435031 | AFBV | 0.003 | |
TCBV
| rs2059943† | 8 | 107140783 | ATCBV | 1.4 × 10-4 | |
TCBV
| rs853256† | 3 | 64290504 | AFBV | 7.5 × 10-4 | |
TCBV
| rs853260† | 3 | 64289592 | AFBV | 4.4 × 10-4 | |
Selected Phenotype : (p < 0.001)
|
SNP
|
Chr
|
Physical Position
|
Gene
|
Phenotype showing strongest association with SNP
|
GEE p-value
|
F1
| rs4733809 | 8 | 1.29E+08 |
TMEM75
| Sim | 1.5 × 10-4 |
F1
| rs3923615 | 11 | 24638108 |
LUZP2
| F1 | 1.1 × 10-4 |
F1
| rs10515155 | 17 | 53836943 |
RNF43
| F1 | 3.6 × 10- |
F1
| rs1204116 | 6 | 62462055 |
KHDRBS2
| F1 | 7.3 × 10-4 |
F1
| rs708891 | 12 | 1.18E+08 |
CCDC60
| F1 | 4.7 × 10-4 |
F1
| rs10515159 | 17 | 54157692 |
RAD51C
| F1 | 3.1 × 10-4 |
F1
| rs10506214 | 12 | 41397957 | F3 | 5.8 × 10-4 | |
F3
| rs608825 | 1 | 2.33E+08 |
EDARADD
| F3 | 5.5 × 10-4 |
F3
| rs957603 | 15 | 38796960 |
RAD51
| F3 | 1.5 × 10-4 |
F3
| rs10506214† | 12 | 41397957 | F3 | 5.8 × 10-4 | |
F3
| rs2109479 | 5 | 56979996 | F3 | 4.2 × 10-4 |