Background
Methods
Data sources
a) | Study | Country | N | Age, years (SD) | Cortisol, nmol/l (SD) | Sampling time |
ORCADES | UK | 1974 | 53.5 (15.7) | 765 (315) | 0830-1030 | |
CROATIA-Korcula | Croatia | 898 | 56.2 (13.9) | 698 (207) | 0800-0900 | |
CROATIA-Split | Croatia | 496 | 45.0 (14.7) | 979 (404) | 0730-0900 | |
CROATIA-Vis | Croatia | 892 | 56.4 (15.5) | 622 (230) | 0730-0900 | |
Rotterdam Study | Netherlands | 6497 | 63.3 (9.6) | 359 (115) | 0800-1100 | |
HBCS1934-44 | Finland | 451 | 60.61 (2.80) | 393 (120) | 0750-1055 | |
NFBC1966 | Finland | 1324 | 31.1 (0.3) | 380 (160) | 0800-1100 | |
ALSPAC | UK | 1567 | 15.43 (0.26) | 486 (174) | 0800-1057 | |
PIVUS | Sweden | 919 | 70.2 (0.17) | 386 (125) | 0800-1000 | |
PREVEND | Netherlands | 1151 | 49.4 (13.0) | 442 (201) | 0800-1100 | |
ET2DS | UK | 1048 | 67.9 (4.2) | 731 (190) | 0800-0830 | |
Raine Study | Australia | 860 | 17.1 (0.29) | 614 (235) | Awakening (before 1000) | |
MrOS Sweden | Sweden | 969 | 75.3 (3.2) | 487 (133) | 0700-1000 | |
VIKING | UK | 2073 | 49.9 (15.2) | 292 (170) | 0800-1030 | |
SHIP | Germany | 910 | 49.8 (13.8) | * | Before 1300 | |
TwinsUK | UK | 5654 | 53.3 (13.8) | * | 0800-1200 | |
KORA | Germany | 1651 | 60.92 (8.7) | * | NA | |
b) | Study | Country | N | Age, years (SD) | Birthweight, g (SD) | Gestational age, weeks (IQR) |
UK Biobank | UK | 190,406 | 25.3 (4.5) | 3227 (477) | NA | |
B58C-WTCCC | UK | 858 | 26.2 (5.2) | 3325 (483) | 40 (40–41) | |
B58C-T1DGC | UK | 836 | 26.1 (5.4) | 3379 (469) | 40 (40–41) | |
DNBC-GOYA | Denmark | 1805 | 29.2 (4.2) | 3643 (495) | 40 (39–41) | |
DNBC-PTB-CONTROL | Denmark | 1656 | 29.9 (4.2) | 3595 (497) | 40 (39–40) | |
MoBa-2008 | Norway | 650 | 28.5 (3.3) | 3679 (430) | 40 (0.9) | |
NFBC1966 | Finland | 2035 | 26.5 (3.7) | 3525 (461) | 40 (2) | |
NTR | Netherlands | 707 | 27.1 (3.7) | 3469 (529) | 40 (38–42) | |
QIMR | Australia | 892 | 24.5 (4.0) | 3344 (532) | NA | |
TWINSUK | UK | 1603 | NA | NA | NA | |
ALSPAC | UK | 6,686 | 28.0 (5.0) | 3468 (475) | 40 (40–41) | |
HAPO | USA | 1280 | 31.5 (5.3) | 3557 (517) | 40 (1.7) | |
EFSOCH | UK | 855 | 30.5 (5.9) | 3506 (472) | 40 (37–43) | |
c) | Study | Country | N | Age, years (SD) | Cortisol, nmol/l (SD) | Sampling time |
EFSOCH | UK | 892 | 30.4 (5.3) | 1010 (234) | 0900 (within 60 minutes) |
Genetic associations with plasma cortisol
Genetic associations with birth weight
Genetic associations with maternal pregnancy cortisol
Data analyses
Adjusting for the fetal genotype
Main MR analyses
IVW analysis adjusting for between SNP correlations
Testing cortisol instrument strength
Testing cortisol instruments relevance to pregnancy
Exploring the possibility of horizontal pleiotropy in the cortisol instrument
Results
Main results and sensitivity analyses
SNP validation
Instrument strength and relevance in pregnancy
Genetic variant (SNP) ID | Number of-participants | Minor allele frequency | Per allele difference (SDs of log-transformed units) in plasma cortisol (95% CI) | R2 | F-Statistic |
---|---|---|---|---|---|
rs11620763 | 25314 | 0.19 | 0.09 (0.06 to 0.11) | 0.0023 | 57.49 |
rs2736898 | 25314 | 0.49 | 0.06 (0.04 to 0.07) | 0.0017 | 43.37 |
rs7146221 | 25314 | 0.45 | 0.05 (0.03 to 0.07) | 0.0013 | 31.87 |
rs9989237a | 25314 | 0.21 | 0.09 (0.07 to 0.10) | 0.0024 | 61.83 |
Possibility of the instrument influencing birth weight through horizontal pleiotropy
Trait | N | Units | Per trait raising allele effect size | Per trait raising allele standard error | P |
---|---|---|---|---|---|
Albumin levels (inverse rank normalized transformed) | 315268 | Quantiles | -0.03354 | 0.00302 | 1.18E-28 |
Albumin levels | 315268 | g/L | -0.08683 | 0.00789 | 3.63E-28 |
SERPINA1 RNA expression in whole blood | 29950 | Z-score matrices | 0.123405 | 0.014223 | 4.09E-18 |
Expression of 39S ribosomal protein L33, mitochondrial | 3301 | Relative concentration | 0.2515 | 0.0298 | 2.82E-17 |
Expression of PH and SEC7 domain-containing protein 1 | 3301 | Relative concentration | 0.1998 | 0.0299 | 2.24E-11 |
Expression of Synaptosomal-associated protein 25 | 3301 | Relative concentration | -0.18 | 0.0299 | 1.78E-09 |
Histidine levels | 114895 | Z-scores | 0.026138 | 0.005102 | 3.00E-07 |
Sex hormone-binding globulin levels adjusted for BMI | 368929 | Log-transformed nmol/l | -0.00535 | 0.00103 | 3.40E-07 |
Sex hormone-binding globulin levels (male only GWAS) | 180726 | Log-transformed nmol/l | -0.00772 | 0.001513 | 6.60E-07 |
Sex hormone-binding globulin levels | 370125 | Log-transformed nmol/l | -0.00515 | 0.001147 | 1.70E-06 |
Sex hormone-binding globulin levels adjusted for BMI (male only GWAS) | 180094 | Log-transformed nmol/l | -0.00712 | 0.001419 | 2.30E-06 |