Background
Methods
Subjects
Phenotype measurements
Survival and mortality-weighted healthy aging index
Glycated hemoglobin (HbA1c), Blood Glucose and Insulin Levels, Leukocyte Telomere Length, Blood Lipid Levels Including Total Cholesterol, HDL Cholesterol, LDL Cholesterol and Triglyceride, BMI, Blood Pressure, Cognitive Function, Stroke, Coronary Heart Disease, Congestive Heart Failure, Cancer, Type 2 Diabetes
Genome-wide SNP array genotyping
Pooled sequencing and indexed custom library preparation
Sequencing
Sequencing alignment, variant calling and filtering
Statistical analyses
Trait exceptionality scores for survival, BMI, blood pressure, blood lipid levels, blood glucose level, blood insulin level, cognitive function, type 2 diabetes, heart disease, cancer, and stroke
Phenotype transformation and covariates adjustment
Single variant association testing
Rare variant testing across genes
Results
Sample characteristics
Phenotype
Sequencing results
Among 464 Candidate genes, 448 genes with 48,918 variants sequenced | |
---|---|
Filter 1: ≥ 5x coverage | 47 ± 36 |
Filter 2: ≥ 45 quality score | 175 ± 53 |
Filter 3: ≥ 60 % call rate | 97 % ± 7 % |
Filter 4: Mendel Errors | MAF dependent |
439 genes with 30,112 variants analyzed |
Single variant analyses
Phenotype (TE Score)
|
chr
|
Position (hg19)
|
rsID
|
gene
|
Function
|
Ref
|
Variant
|
MAF
|
N
|
Beta
|
SE
|
P-value
|
---|---|---|---|---|---|---|---|---|---|---|---|---|
Survival | 10 | 105642272 |
OBFC1
| UTR3 | C | G | 0.002 | 810 | 3.58 | 0.71 | 6.2E-7 | |
Cancer | 15 | 99501295 |
IGF1R
| UTR3 | A | G | 0.007 | 4210 | 0.58 | 0.13 | 3.7E-6 | |
HDL Cholesterol | 16 | 57005301 | rs1532625 |
CETP
| intron | T | C | 0.38 | 3053 | 0.19 | 0.03 | 2.4E-13 |
16 | 57015091 | rs5880 |
CETP
| nsyn-exon | C | G | 0.047 | 4049 | −0.32 | 0.06 | 1.2E-8 | |
16 | 57017319 | rs1800777 |
CETP
| nsyn-exon | A | G | 0.029 | 3982 | −0.40 | 0.07 | 8.1E-9 | |
LDL Cholesterol | 6 | 152679594 | rs62426382 |
SYNE1
| syn-exon | G | A | 0.016 | 4035 | 0.45 | 0.09 | 1.6E-6 |
19 | 45396144 | rs11556505 |
TOMM40
| syn-exon | T | C | 0.10 | 4018 | −0.19 | 0.04 | 1.5E-6 | |
19 | 45397229 | rs1160983 |
TOMM40
| syn-exon | A | G | 0.02 | 2686 | 0.53 | 0.10 | 1.2E-7 | |
Triglyceride | 11 | 116703640 | rs5128 |
APOC3
| UTR3 | G | C | 0.09 | 4003 | −0.21 | 0.04 | 1.2E-7 |
chr
|
Position (hg19)
|
rsID
|
gene
|
Function
|
Ref
|
Variant
|
Minor Allele Count
|
MAF
|
N
|
Beta
|
SE
|
P-value
|
---|---|---|---|---|---|---|---|---|---|---|---|---|
7 | 17385235 |
AHR
| UTR3 | A | G | 5 | 0.0006 | 810 | 3.58 | 0.71 | 6.18E-07 | |
11 | 27680107 | rs8192466 |
BDNF
| nsyn-exonic | A | G | 8 | 0.0009 | 810 | 5.02 | 1.01 | 7.41E-07 |
16 | 57015065 |
CETP
| intronic | T | C | 3 | 0.0004 | 809 | 5.00 | 1.01 | 8.69E-07 | |
1 | 207813049 |
CR1
| UTR3 | A | G | 5 | 0.0006 | 810 | 5.02 | 1.01 | 7.41E-07 | |
8 | 6735377 |
DEFB1
| nsyn-exonic | T | C | 1 | 0.0001 | 809 | 5.03 | 1.01 | 7.22E-07 | |
10 | 71139772 |
HK1
| nsyn-exonic | T | C | 1 | 0.0001 | 794 | 5.04 | 1.01 | 6.53E-07 | |
1 | 209959231 |
IRF6
| UTR3 | G | A | 4 | 0.0005 | 810 | 3.58 | 0.71 | 6.18E-07 | |
21 | 35195906 |
ITSN1
| syn-exonic | A | C | 1 | 0.0001 | 810 | 5.02 | 1.01 | 7.41E-07 | |
15 | 100256347 |
MEF2A
| UTR3 | C | T | 2 | 0.0002 | 810 | 5.02 | 1.01 | 7.41E-07 | |
1 | 12073445 |
MFN2
| UTR3 | T | C | 3 | 0.0003 | 810 | 5.07 | 1.01 | 6.10E-07 | |
4 | 100544175 |
MTTP
| UTR3 | G | A | 1 | 0.0001 | 810 | 5.07 | 1.01 | 6.10E-07 | |
2 | 1794502 |
MYT1L
| UTR3 | T | C | 1 | 0.0001 | 810 | 5.02 | 1.01 | 7.41E-07 | |
16 | 50267300 |
PAPD5
| UTR3 | T | C | 4 | 0.0005 | 810 | 3.58 | 0.71 | 6.18E-07 | |
2 | 223158616 |
PAX3
| UTR3 | T | C | 3 | 0.0003 | 810 | 3.58 | 0.71 | 6.18E-07 | |
7 | 95214257 |
PDK4
| UTR3 | G | A | 2 | 0.0002 | 810 | 5.07 | 1.01 | 6.10E-07 | |
5 | 149206403 | rs374853976 |
PPARGC1B
| syn-exonic | A | G | 1 | 0.0001 | 714 | 5.07 | 1.00 | 4.72E-07 |
10 | 99130549 |
RRP12
| nsyn-exonic | T | C | 1 | 0.0001 | 780 | 5.02 | 1.01 | 7.66E-07 | |
17 | 28525015 | rs199875985 |
SLC6A4
| UTR3 | G | A | 1 | 0.0001 | 810 | 5.07 | 1.01 | 6.10E-07 |
15 | 67479818 | rs144245324 |
SMAD3
| syn-exonic | T | C | 3 | 0.0004 | 767 | 5.02 | 1.02 | 9.22E-07 |
3 | 24163883 |
THRB
| UTR3 | T | C | 7 | 0.0008 | 810 | 3.58 | 0.71 | 6.18E-07 | |
14 | 81610971 |
TSHR
| UTR3 | A | G | 2 | 0.0002 | 810 | 5.07 | 1.01 | 6.10E-07 | |
21 | 46189291 |
UBE2G2
| UTR3 | T | C | 3 | 0.0004 | 810 | 5.02 | 1.01 | 7.41E-07 | |
19 | 9770038 |
ZNF562
| intronic | T | G | 2 | 0.0002 | 810 | 3.58 | 0.71 | 6.18E-07 |
Analyses of multiple variants across genes
Phenotype
|
Gene
|
RefSeq
|
Total Exons
|
Analyzed Exons
|
Indiv Seq (#)
|
Variants called (#)
|
Ped (#)
|
P-value (PWST)
|
P-value (Skat)
|
---|---|---|---|---|---|---|---|---|---|
Healthy Aging Index (Mortality Weighted) |
GSK3B
| NM_002093 | 12 | 8 | 3217 | 77 | 121 | 1.00E-4 | 2.08E-4 |
Diastolic Blood Pressure |
NOTCH1
| NM_017617 | 34 | 3 | 4112 | 55 | 78 | 1.00E-4 | 5.37E-3 |
HDL Cholesterol |
TP53
| NM_000546 | 11 | 6 | 4073 | 21 | 86 | 1.00E-4 | 8.05E-3 |