Background
Methods
Cohort and sample selection
Characteristic | Discovery Cohort (n = 200) | Validation Cohort (n = 567) | p-value |
---|---|---|---|
Age at delivery (years) | 33.4 (32.8, 34.0) | 33.2 (32.8, 33.6) | 0.6 |
Gestational age at delivery (weeks) | 40.1 (39.9, 40.3) | 39.8 (39.7, 40.0) | 0.02 |
Parity (n) | 1.7 (1.6, 1.8) | 1.7 (1.6, 1.8) | 0.6 |
Pre-pregnancy BMI (kg/m2) | 23.9 (23.2, 24.6) | 24.2 (23.8, 24.6) | 0.5 |
Weight gain during pregnancy (kg) | 9.2 (8.0, 10.4) | 9.0 (8.2, 9.7) | 0.8 |
Week 28 OGTT fasting glucose concentration (mmol/L) | 4.3 (4.2, 4.4) | 4.3 (4.3, 4.3) | 0.9 |
Week 28 OGTT 60 min. glucose concentration (mmol/L) | 6.4 (6.2, 6.7) | 6.6 (6.5, 6.8) | 0.1 |
Week 28 fasting insulin concentration (pmol/L) | 44.9 (41.7, 48.4) | 45.6 (43.7, 47.6) | 0.7 |
Week 28 fasting insulin resistance (HOMA IR) | 0.915 (0.850, 0.985) | 0.925 (0.886, 0.965) | 0.8 |
Carrying a male fetus (%) | 49.2 | 52.6 | 0.4 |
Smoking during pregnancy (%) | 2.6 | 4.9 | 0.2 |
Gene selection and genetics
Gene | No. of SNPs | Single nucleotide polymorphisms |
---|---|---|
DLK1
| 5 | rs12147008, rs7155375, rs10139403, rs1802710, rs7147586 |
FAM99A*
| 7 | rs4752779, rs4752781, rs11600502, rs10839220, rs11607954, rs1489945, rs7131362 |
GNAS
| 20 | rs6123832, rs965808, rs6128441, rs6026561, rs6026560, rs12625436, rs4810148, rs7271854, rs6100260, rs6026576, rs6128461, rs6123837, rs13831, rs234630, rs919196, rs3730168, rs919197, rs7121, rs234623, rs234621 |
GRB10
| 17 | rs4245555, rs12669770, rs7802879, rs7777754, rs2715129, rs3807549, rs2299150, rs11769934, rs2237441, rs1468450, rs6948959, rs980716, rs2715116, rs737292, rs7794604, rs17133917, rs2237450 |
H19
| 13 | rs2071094, rs2735466, rs7950932, rs217222, rs217727, rs2251375, rs217228, rs3741216, rs1706879, rs2735971, rs7950715, rs7950787, rs12417375 |
IGF2*
| 17 | rs6578987, *rs734351, *rs4341514, rs680, *rs3741212, *rs11603378, *rs3213216, *rs10770125, *rs3741205, *rs3741206, rs1004446, *rs4320932, *rs3842752, *rs7924316, *rs7483056, *rs6356, *rs10743152 |
INS*
| 16 | *rs734351, *rs4341514, rs2585, *rs3741212, *rs11603378, *rs3213216, *rs10770125, *rs3741205, *rs3741206, *rs4320932, rs3741211, *rs3842752, *rs7924316, *rs7483056, *rs6356, *rs10743152 |
KCNQ1OT1*
| 14 | rs231352, rs463924, rs4930005, rs231841, rs10832514, rs756852, rs7128926, rs10832430, rs231361, rs760419, rs9666537, rs7929804, rs10766218, rs6578283 |
MEST
| 6 | rs12706933, rs13234660, rs765205, rs13225903, rs1047456, rs10954272 |
NNAT
| 3 | rs6066671, rs12481150, rs6019103 |
PEG3*
| 8 | rs17207579, rs11084466, *rs2079877, *rs7256072, *rs382592, rs758752, rs7248098, *rs1860565 |
PEG10
| 5 | rs1568214, rs13073, rs1533831, rs6948099, rs6465422 |
PLAGL1
| 20 | rs12528289, rs9484833, rs1884087, rs10499846, rs2268440, rs6930726, rs7770529, rs2268443, rs2876578, rs9373409, rs2268445, rs17073273, rs9403542, rs9484836, rs6570599, rs2328537, rs9321957, rs6937128, rs9767615, rs2207851 |
SGCE
| 2 | rs1879854, rs7778237 |
SNRPN
| 12 | rs7164801, rs17114774, rs7171320, rs1453556, rs4028398, rs1982981, rs736008, rs9806682, rs7164989, rs8042562, rs12592279, rs8029318 |
ZIM2*
| 8 | *rs2079877, rs12981689, rs1476830, *rs7256072, *rs382592, *rs1860565, rs2286751, rs10401139 |
Paternal Genotype | Maternal Genotype | Fetal Genotype | Paternally-transmitted Allele | Maternally-transmitted Allele |
---|---|---|---|---|
A/A | A/A | A/A | A | A |
A/A | A/a | A/A | A | A |
A/A | A/a | A/a | A | a |
A/A | a/a | A/a | A | a |
A/a | A/A | A/A | A | A |
A/a | A/A | A/a | a | A |
A/a | A/a | A/A | A | A |
A/a | A/a | A/a | Uninformative | Uninformative |
A/a | A/a | a/a | a | a |
A/a | a/a | A/a | A | a |
A/a | a/a | a/a | a | a |
a/a | A/A | A/a | a | A |
a/a | A/a | A/a | a | A |
a/a | A/a | a/a | a | a |
a/a | a/a | a/a | a | a |
Lipid profiling: Sample extraction and mass spectrometry
Liquid chromatography–mass spectrometry
Other assays and calculations
Statistical power
Statistical analyses
Results
Associations between fetal imprinted gene alleles and the maternal lipid profile around week 15 of pregnancy
SNP | Gene | Parental Transmission | Lipid | VIP Score of lipid species* | Discovery Cohort | Validation Cohort | Meta-Analysis | |||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
R | p-value | n | R | p-value | n | R | p-value | |||||
rs10839220 |
KRTAP5–6
| Maternal | TG(44:1) | 3.4 | 0.175 | 0.03 | 163 | 0 | 0.96 | 197 | 0.09 (− 0.09, 0.25) | 0.17 |
rs10839220 |
KRTAP5–6
| Maternal | LysoPCP(18:0) | 2.8 | 0.243 | 1.8 × 10− 3 | 163 | 0.092 | 0.16 | 233 | 0.16 (0.01, 0.31) | 0.02 |
rs10839220 |
KRTAP5–6
| Maternal | PE(34:0) | 2.2 | 0.279 | 3.2 × 10−4 | 163 | 0.014 | 0.85 | 233 | 0.15 (−0.12, 0.39) | 0.14 |
rs10839220 |
KRTAP5–6
| Maternal | DG(36:3) | 2.1 | 0.271 | 4.6 × 10−4 | 163 | 0.118 | 0.09 | 209 | 0.19 (0.04, 0.34) | 7.4 × 10−3 |
rs4752779 |
FAM99B
| Maternal | TG(44:1) | 3.2 | 0.161 | 0.03 | 173 | 0.030 | 0.67 | 201 | 0.09 (−0.04, 0.22) | 0.08 |
rs7131362 |
FAM99A
| Maternal | TG(44:1) | 4.7 | 0.257 | 9.7 × 10−4 | 161 | 0.114 | 0.12 | 190 | 0.18 (0.04, 0.32) | 6.2 × 10−3 |
rs7131362 |
FAM99A
| Maternal | TG(48:0) | 2.1 | 0.197 | 0.01 | 161 | 0 | 0.95 | 217 | 0.10 (−0.10, 0.28) | 0.17 |
rs17073273 |
PLAGL1
| Maternal | TG(44:1) | 3.5 | 0.181 | 0.02 | 175 | 0.014 | 0.83 | 206 | 0.09 (−0.07, 0.25) | 0.13 |
rs17073273 |
PLAGL1
| Maternal | TG(55:9) | 2.7 | 0.234 | 1.8 × 10−3 | 175 | 0.079 | 0.23 | 235 | 0.15 (0.00, 0.30) | 0.03 |
rs17073273 |
PLAGL1
| Maternal | TG(48:0) | 2.5 | 0.226 | 2.6 × 10−3 | 175 | 0.035 | 0.59 | 235 | 0.13 (−0.06, 0.31) | 0.09 |
rs2268445 |
PLAGL1
| Maternal | TG(44:1) | 3.6 | 0.189 | 0.01 | 176 | 0.035 | 0.62 | 212 | 0.11 (−0.04, 0.26) | 0.08 |
rs7950932 |
H19
| Paternal | TG(44:1) | 2.6 | 0.167 | 0.02 | 183 | 0.117 | 0.10 | 203 | 0.14 (0.04, 0.24) | 2.3 × 10−3 |
SNP | Gene | Lipid | Discovery Cohort | Validation Cohort | Meta-Analysis | |||||
---|---|---|---|---|---|---|---|---|---|---|
R | p-value | n | R | p-value | n | R | p-value | |||
rs10839220 |
KRTAP5–6
| TG(44:1) | 0.157 | 0.04 | 179 | 0.017 | 0.78 | 225 | 0.08 (−0.05, 0.22) | 0.12 |
rs10839220 |
KRTAP5–6
| LysoPCP(18:0) | 0.205 | 5.8 × 10−3 | 179 | 0 | 0.92 | 267 | 0.10 (−0.10, 0.29) | 0.17 |
rs10839220 |
KRTAP5–6
| PE(34:0) | 0.194 | 9.2 × 10−3 | 179 | 0.051 | 0.41 | 267 | 0.12 (− 0.02, 0.25) | 0.05 |
rs10839220 |
KRTAP5–6
| DG(36:3) | 0.224 | 2.6 × 10−3 | 179 | 0.062 | 0.34 | 240 | 0.14 (−0.02, 0.29) | 0.04 |
rs4752779 |
FAM99B
| TG(44:1) | 0.102 | 0.17 | 180 | 0.045 | 0.51 | 227 | 0.07 (−0.03, 0.17) | 0.08 |
rs7131362 |
FAM99A
| TG(44:1) | 0.222 | 2.9 × 10− 3 | 178 | 0.041 | 0.54 | 221 | 0.13 (−0.05, 0.30) | 0.08 |
rs7131362 |
FAM99A
| TG(48:0) | 0.150 | 0.05 | 178 | 0.030 | 0.64 | 251 | 0.08 (−0.03, 0.20) | 0.08 |
rs17073273 |
PLAGL1
| TG(44:1) | 0.042 | 0.56 | 188 | 0.033 | 0.61 | 234 | 0.04 (−0.06, 0.13) | 0.23 |
rs17073273 |
PLAGL1
| TG(55:9) | 0.125 | 0.09 | 188 | 0.117 | 0.06 | 267 | 0.12 (0.03, 0.21) | 5.2 × 10−3 |
rs17073273 |
PLAGL1
| TG(48:0) | 0.084 | 0.25 | 188 | 0.057 | 0.35 | 267 | 0.07 (− 0.02, 0.16) | 0.07 |
rs2268445 |
PLAGL1
| TG(44:1) | 0.046 | 0.54 | 187 | 0.071 | 0.28 | 231 | 0.06 (−0.04, 0.16) | 0.11 |
SNP | Gene | Lipid | Discovery Cohort | Validation Cohort | Meta-Analysis | |||||
---|---|---|---|---|---|---|---|---|---|---|
R | p-value | n | R | p-value | n | R | p-value | |||
rs10839220 |
KRTAP5–6
| TG(44:1) | 0.113 | 0.16 | 154 | 0.067 | 0.38 | 179 | 0.09 (−0.02, 0.19) | 0.05 |
rs10839220 |
KRTAP5–6
| LysoPCP(18:0) | 0.095 | 0.24 | 154 | 0.114 | 0.10 | 213 | 0.11 (0, 0.21) | 0.02 |
rs10839220 |
KRTAP5–6
| PE(34:0) | 0.068 | 0.54 | 154 | 0.042 | 0.40 | 213 | 0.05 (−0.05, 0.15) | 0.16 |
rs10839220 |
KRTAP5–6
| DG(36:3) | 0.122 | 0.13 | 154 | 0 | 0.98 | 190 | 0.06 (−0.06, 0.17) | 0.18 |
rs4752779 |
FAM99B
| TG(44:1) | 0.020 | 0.81 | 161 | 0.054 | 0.47 | 185 | 0.04 (−0.07, 0.14) | 0.24 |
rs7131362 |
FAM99A
| TG(44:1) | 0.119 | 0.14 | 153 | 0.050 | 0.51 | 175 | 0.08 (−0.03, 0.19) | 0.07 |
rs7131362 |
FAM99A
| TG(48:0) | 0.080 | 0.43 | 153 | 0.065 | 0.26 | 198 | 0.07 (−0.03, 0.18) | 0.09 |
rs17073273 |
PLAGL1
| TG(44:1) | 0.131 | 0.09 | 170 | 0.024 | 0.74 | 201 | 0.07 (−0.03, 0.18) | 0.09 |
rs17073273 |
PLAGL1
| TG(55:9) | 0 | 0.98 | 170 | 0.123 | 0.06 | 228 | 0.07 (−0.05, 0.19) | 0.13 |
rs17073273 |
PLAGL1
| TG(48:0) | 0.094 | 0.22 | 170 | 0.067 | 0.31 | 228 | 0.08 (−0.02, 0.18) | 0.06 |
rs2268445 |
PLAGL1
| TG(44:1) | 0.092 | 0.23 | 172 | 0.022 | 0.76 | 201 | 0.05 (−0.05, 0.16) | 0.15 |
SNP | Gene | Parental Transmission | Lipid | Discovery Cohort | Validation Cohort | Meta-Analysis | |||||
---|---|---|---|---|---|---|---|---|---|---|---|
R | p-value | n | R | p-value | n | R | p-value | ||||
rs10839220 |
KRTAP5–6
| Paternal | TG(44:1) | 0.12 | 0.14 | 161 | 0.08 | 0.26 | 200 | 0.10 (−0.01, 0.20) | 0.03 |
rs10839220 |
KRTAP5–6
| Paternal | LysoPCP(18:0) | 0.07 | 0.40 | 161 | 0.12 | 0.07 | 235 | 0.07 (−0.03, 0.17) | 0.08 |
rs10839220 |
KRTAP5–6
| Paternal | PE(34:0) | 0.10 | 0.20 | 161 | 0.11 | 0.10 | 235 | 0.11 (0.01, 0.20) | 0.02 |
rs10839220 |
KRTAP5–6
| Paternal | DG(36:3) | 0.05 | 0.53 | 161 | 0.18 | 8.4 × 10−3 | 213 | 0.12 (−0.01, 0.25) | 0.03 |
rs4752779 |
FAM99B
| Paternal | TG(44:1) | 0.03 | 0.66 | 174 | 0.04 | 0.61 | 205 | 0.04 (−0.07, 0.14) | 0.25 |
rs7131362 |
FAM99A
| Paternal | TG(44:1) | 0.05 | 0.57 | 159 | 0.01 | 0.86 | 204 | 0.03 (−0.08, 0.13) | 0.30 |
rs7131362 |
FAM99A
| Paternal | TG(48:0) | 0.03 | 0.68 | 159 | 0.03 | 0.64 | 232 | 0.03 (−0.07, 0.13) | 0.26 |
rs17073273 |
PLAGL1
| Paternal | TG(44:1) | 0.14 | 0.07 | 174 | 0.08 | 0.26 | 216 | 0.11 (0.01, 0.20) | 0.02 |
rs17073273 |
PLAGL1
| Paternal | TG(55:9) | 0.13 | 0.08 | 174 | 0.03 | 0.66 | 248 | 0.07 (−0.03, 0.17) | 0.08 |
rs17073273 |
PLAGL1
| Paternal | TG(48:0) | 0.19 | 0.01 | 174 | 0.10 | 0.10 | 248 | 0.14 (0.04, 0.23) | 2.4 × 10−3 |
rs2268445 |
PLAGL1
| Paternal | TG(44:1) | 0.14 | 0.06 | 177 | 0.14 | 0.04 | 218 | 0.14 (0.04, 0.24) | 2.7 × 10−3 |
rs7950932 |
H19
| Maternal | TG(44:1) | 0.09 | 0.21 | 183 | 0.09 | 0.22 | 209 | 0.09 (−0.01, 0.19) | 0.04 |
Associations between the abundance of TG(44:1) at around week 15 of pregnancy and clinically significant parameters
Biomarker | Discovery Cohort | Validation Cohort | Meta-Analysis | |||||
---|---|---|---|---|---|---|---|---|
R | p-value | n | R | p-value | n | R | p-value | |
Pre-pregnancy BMI | −0.10 | 0.21 | 170 | −0.06 | 0.31 | 356 | −0.07 (− 0.16, 0.01) | 0.05 |
Fasting glucose concentration | 0.04 | 0.54 | 195 | 0.11 | 0.02 | 478 | 0.09 (0.01, 0.16) | 9.9 × 10−3 |
Glucose concentration 60 min. post 75 g load | 0.16 | 0.03 | 195 | 0.05 | 0.26 | 478 | 0.09 (−0.01, 0.19) | 0.04 |
Fasting insulin concentration | 0.03 | 0.65 | 189 | 0.10 | 0.03 | 476 | 0.08 (0, 0.16) | 0.02 |
HOMA IR | 0.03 | 0.65 | 189 | 0.12 | 8.8 × 10−3 | 475 | 0.09 (0.01, 0.17) | 0.01 |
HOMA B | 0.03 | 0.72 | 189 | 0.05 | 0.26 | 475 | 0.04 (−0.03, 0.12) | 0.13 |