Background
First Author | Title |
---|---|
Ramachandran S. Vasan | |
Daniel Levy | |
Christopher J. O'Donnell | |
Martin G. Larson | |
Joanne M. Murabito | |
Christopher Newton-Cheh | |
Jemma B. Wilk | |
Daniel J. Gottlieb | |
Shih-Jen Hwang | |
Emelia J. Benjamin | |
Qiong Yang | |
Kathryn L. Lunetta | |
Douglas P. Kiel | |
Sudha Seshadri | |
James B. Meigs | |
Sekar Kathiresan | |
Caroline S. Fox |
Methods
Study sample
Phenotype definition & methods
Genotyping methods
Statistical analysis methods
Data cleaning
Linkage analyses
Association testing
Results
Participant characteristics
Original Cohort Men | Original Cohort Women | Offspring Cohort Men | Offspring Cohort Women | |
---|---|---|---|---|
N = 90 | N = 168 | N = 527 | N = 560 | |
Age, years | 35 ± 4 | 35 ± 4 | 31 ± 10 | 32 ± 10 |
(Limits) | (30–46) | (29–48) | (11–62) | (5–59) |
Body Mass Index, kg/m2 | 25.7 ± 3.2 | 23.9 ± 3.6 | 26.0 ± 3.9 | 23.6 ± 4.3 |
Obese (BMI 30 ≥kg/m2), % | 7.8 | 6.0 | 13.3 | 8.2 |
Systolic Blood Pressure, mm Hg | 129 ± 13 | 120 ± 12 | 124 ± 14 | 115 ± 14 |
Diastolic Blood Pressure, mm Hg | 81 ± 9 | 76 ± 8 | 81 ± 10 | 75 ± 10 |
Antihypertensive Medication, % | 0 | 0 | 1.7 | 1.4 |
Hypertension, % | 22.2 | 8.9 | 15.0 | 6.8 |
Current Smoking, % | 61.1 | 42.3 | 40.0 | 41.3 |
Blood Glucose, mg/dL | 78 ± 13 | 78 ± 11 | 102 ± 10 | 97 ± 9 |
Prevalent Diabetes, % | 0 | 0 | 0.6 | 0.4 |
Total Cholesterol, mg/dL | 220 ± 44 | 194 ± 37 | 192 ± 37 | 185 ± 36 |
HDL Cholesterol, mg/dL | N/A | N/A | 44.9 ± 11.0 | 56.4 ± 13.9 |
Lipid Lowering Medication, % | 0 | 0 | 0.2 | 0.5 |
Hemoglobin, g/dL | 14.3 ± 1.2 | 12.3 ± 1.1 | 15.5 ± 1.0 | 13.5 ± 1.0 |
Forced Vital Capacity, dL | 40 ± 7 | 28 ± 6 | 45 ± 8 | 32 ± 5 |
Prevalent CVD, % | 0 | 0 | 5.5 | 2.6 |
Format of the FHS 100K manuscripts
SNPs with MAF ≥ 10%, HWE p ≥ 0.001 and Genotyping Call Rate ≥ 80% | |||||||||
---|---|---|---|---|---|---|---|---|---|
Nominal alpha level | |||||||||
# SNPs | 0.05 | 0.01 | 0.001 | 1 × 10-4 | 1 × 10-5 | 1 × 10-6 | 1 × 10-7 | 1 × 10-8 | |
Metabolic Traits* | |||||||||
Mean† FBAT | 70987 | 0.050 | 0.010 | 8.5 × 10-4 | 7.3 × 10-5 | 5.1 × 10-6 | 6.1 × 10-7 | 1.4 × 10-7 | 0 |
Min† FBAT | 0.046 | 0.008 | 4.4 × 10-4 | 0 | 0 | 0 | 0 | 0 | |
Max† FBAT | 0.056 | 0.012 | 1.5 × 10-3 | 2.7 × 10-4 | 5.6 × 10-5 | 4.2 × 10-5 | 2.8 × 10-5 | 0 | |
Mean GEE | 70987 | 0.058 | 0.013 | 1.6 × 10-3 | 2.3 × 10-4 | 3.7 × 10-5 | 7.9 × 10-6 | 1.9 × 10-6 | 1.0 × 10-7 |
Min GEE | 0.051 | 0.010 | 9.2 × 10-4 | 5.6 × 10-5 | 0 | 0 | 0 | 0 | |
Max GEE | 0.081 | 0.022 | 3.3 × 10-3 | 6.6 × 10-4 | 1.4 × 10-4 | 8.5 × 10-5 | 5.6 × 10-5 | 1.4 × 10-5 | |
CVD Events* | |||||||||
Mean FBAT | 70987 | 0.050 | 0.009 | 6.6 × 10-4 | 4.4 × 10-5 | 4.0 × 10-6 | 0 | 0 | 0 |
Min FBAT | 0.047 | 0.006 | 1.7 × 10-4 | 0 | 0 | 0 | 0 | 0 | |
Max FBAT | 0.053 | 0.010 | 9.4 × 10-4 | 8.5 × 10-5 | 1.4 × 10-5 | 0 | 0 | 0 | |
Mean GEE | 70987 | 0.054 | 0.012 | 1.4 × 10-3 | 1.8 × 10-4 | 2.4 × 10-5 | 6.7 × 10-6 | 2.7 × 10-6 | 6.7 × 10-7 |
Min GEE | 0.046 | 0.009 | 7.9 × 10-4 | 4.2 × 10-5 | 0 | 0 | 0 | 0 | |
Max GEE | 0.062 | 0.015 | 2.5 × 10-3 | 5.9 × 10-4 | 1.3 × 10-4 | 5.6 × 10-5 | 2.8 × 10-5 | 1.4 × 10-5 | |
All SNPs posted on website http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007 | |||||||||
Metabolic Traits* | |||||||||
Mean FBAT | 100584 | 0.050 | 0.009 | 7.7 × 10-4 | 6.3 × 10-5 | 4.3 × 10-6 | 5.7 × 10-7 | 1.2 × 10-7 | 0 |
Min FBAT | 0.046 | 0.008 | 4.4 × 10-4 | 0 | 0 | 0 | 0 | 0 | |
Max FBAT | 0.054 | 0.011 | 1.3 × 10-3 | 2.2 × 10-4 | 5.0 × 10-5 | 3.0 × 10-5 | 2.0 × 10-5 | 0 | |
Mean GEE | 101944 | 0.061 | 0.015 | 2.4 × 10-3 | 5.5 × 10-4 | 1.9 × 10-4 | 8.4 × 10-5 | 4.3 × 10-5 | 2.5 × 10-5 |
Min GEE | 0.052 | 0.012 | 1.5 × 10-3 | 1.9 × 10-4 | 3.0 × 10-5 | 0 | 0 | 0 | |
Max GEE | 0.082 | 0.025 | 1.1 × 10-2 | 6.8 × 10-3 | 4.3 × 10-3 | 2.6 × 10-3 | 1.7 × 10-3 | 9.4 × 10-4 | |
CVD Events* | |||||||||
Mean FBAT | 101060 | 0.048 | 0.008 | 5.9 × 10-4 | 3.5 × 10-5 | 3.3 × 10-6 | 0 | 0 | 0 |
Min FBAT | 0.043 | 0.005 | 1.2 × 10-4 | 0 | 0 | 0 | 0 | 0 | |
Max FBAT | 0.052 | 0.010 | 9.1 × 10-4 | 9.9 × 10-5 | 1.0 × 10-5 | 0 | 0 | 0 | |
Mean GEE | 103194 | 0.059 | 0.016 | 3.4 × 10-3 | 1.1 × 10-3 | 4.7 × 10-4 | 2.0 × 10-4 | 9.5 × 10-5 | 4.4 × 10-5 |
Min GEE | 0.050 | 0.011 | 1.1 × 10-3 | 1.3 × 10-4 | 2.9 × 10-5 | 0 | 0 | 0 | |
Max GEE | 0.078 | 0.033 | 1.4 × 10-2 | 7.1 × 10-3 | 3.6 × 10-3 | 1.6 × 10-3 | 7.8 × 10-4 | 3.3 × 10-4 |
Nominal Type I Error | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|
SNP QTL Heritability | Effect Size (SD)* | Model | 0.05 | 0.01 | 0.001 | 10-4 | 10-5 | 10-6 | 10-7 | 10-8 |
100% phenotype available (n = 1345)
| ||||||||||
1% | 0.24 | GEE | 0.977 | 0.919 | 0.78 | 0.60 | 0.43 | 0.27 | 0.17 | 0.10 |
2% | 0.33 | GEE | 1 | 1.00 | 0.99 | 0.97 | 0.91 | 0.84 | 0.72 | 0.59 |
3% | 0.41 | GEE | 1 | 1 | 1 | 0.998 | 0.992 | 0.985 | 0.957 | 0.918 |
4% | 0.47 | GEE | 1 | 1 | 1 | 1 | 1 | 1 | 0.996 | 0.991 |
5% | 0.53 | GEE | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 |
~80% subjects have phenotype(~20% missing at random): Sample size = 1076
| ||||||||||
1% | 0.24 | GEE | 0.934 | 0.836 | 0.631 | 0.427 | 0.261 | 0.149 | 0.074 | 0.041 |
2% | 0.33 | GEE | 1.00 | 0.99 | 0.97 | 0.93 | 0.82 | 0.66 | 0.51 | 0.37 |
3% | 0.41 | GEE | 1 | 1 | 0.998 | 0.993 | 0.976 | 0.938 | 0.85 | 0.753 |
4% | 0.47 | GEE | 0.998 | 0.998 | 0.998 | 0.998 | 0.991 | 0.984 | 0.971 | 0.949 |
5% | 0.53 | GEE | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 0.99 |
~60% subjects have phenotype(~40% missing at random): Sample size = 783
| ||||||||||
1% | 0.24 | GEE | 0.879 | 0.737 | 0.48 | 0.281 | 0.137 | 0.055 | 0.023 | 0.008 |
2% | 0.33 | GEE | 0.992 | 0.96 | 0.88 | 0.744 | 0.591 | 0.433 | 0.293 | 0.186 |
3% | 0.41 | GEE | 1 | 1 | 0.982 | 0.945 | 0.874 | 0.754 | 0.602 | 0.467 |
4% | 0.47 | GEE | 1 | 1 | 1 | 0.998 | 0.981 | 0.95 | 0.884 | 0.797 |
5% | 0.53 | GEE | 1 | 1 | 0.999 | 0.997 | 0.996 | 0.982 | 0.964 | 0.931 |
SNP allele frequencies and distribution
P-value distribution
Power estimations for population-based association approach
Synthetic strategies
Some results of interest
Overlap of linkage and association results
SNPs overlapping across phenotypes
Replication of prior associations
Replication of results from other genome-wide studies
Discussion
Phenotype working group/manuscript | Trait | SNP rs ID* | Chr | Physical location (bp) | GEE P-value | FBAT P-value | IN/NEAR gene |
---|---|---|---|---|---|---|---|
Select biomarkers [33] | Monocyte chemoattractant protein-1 | rs2494250 | 1 | 156,091,324 | 1.0*10-14 | 3.5*10-8 |
FCER1A, OR10J3
|
Monocyte chemoattractant protein-1 | rs4128725 | 1 | 156,219,032 | 3.7*10-12 | 3.3*10-8 |
OR10J1
| |
C-reactive protein average exams 2,6,7 | rs2794520 | 1 | 156,491,889 | 2.8*10-8 | 4.3*10-5 |
CRP
| |
C-reactive protein average exams 2,6,7 | rs2808629 | 1 | 156,489,869 | 3.2*10-8 | 4.8*10-5 |
CRP
| |
Kidney/Endocrine [42] | Cystatin C | rs1158167 | 20 | 23,526,189 | 8.5*10-09 | 0.006 |
CST9L|CST9|CST3
|
Diabetes [38] | 28-year mean fasting plasma glucose | rs2722425 | 8 | 40,603,396 | 2.0*10-8 | 0.005 |
ZMAT4
|
Sleep and circadian [26] | Epworth sleepiness scale | rs1823068 | 5 | 58,711,806 | 2.5*10-8 | 0.069 |
PDE4D
|
Neurology [37] | Total Cerebral Brain Volume (ATCBV) | rs1970546 | 20 | 59287333 | 4.0*10-8 | 0.005 |
CDH4
|
Hemostatic factors [34] | Factor VII | rs561241 | 13 | 112,808,035 | 4.5*10-16 | 3.4*10-4 |
F7
|