Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors.
Warrington NM., Beaumont RN., Horikoshi M., Day FR., Helgeland Ø., Laurin C., Bacelis J., Peng S., Hao K., Feenstra B., Wood AR., Mahajan A., Tyrrell J., Robertson NR., Rayner NW., Qiao Z., Moen G-H., Vaudel M., Marsit CJ., Chen J., Nodzenski M., Schnurr TM., Zafarmand MH., Bradfield JP., Grarup N., Kooijman MN., Li-Gao R., Geller F., Ahluwalia TS., Paternoster L., Rueedi R., Huikari V., Hottenga J-J., Lyytikäinen L-P., Cavadino A., Metrustry S., Cousminer DL., Wu Y., Thiering E., Wang CA., Have CT., Vilor-Tejedor N., Joshi PK., Painter JN., Ntalla I., Myhre R., Pitkänen N., van Leeuwen EM., Joro R., Lagou V., Richmond RC., Espinosa A., Barton SJ., Inskip HM., Holloway JW., Santa-Marina L., Estivill X., Ang W., Marsh JA., Reichetzeder C., Marullo L., Hocher B., Lunetta KL., Murabito JM., Relton CL., Kogevinas M., Chatzi L., Allard C., Bouchard L., Hivert M-F., Zhang G., Muglia LJ., Heikkinen J., EGG Consortium None., Morgen CS., van Kampen AHC., van Schaik BDC., Mentch FD., Langenberg C., Luan J., Scott RA., Zhao JH., Hemani G., Ring SM., Bennett AJ., Gaulton KJ., Fernandez-Tajes J., van Zuydam NR., Medina-Gomez C., de Haan HG., Rosendaal FR., Kutalik Z., Marques-Vidal P., Das S., Willemsen G., Mbarek H., Müller-Nurasyid M., Standl M., Appel EVR., Fonvig CE., Trier C., van Beijsterveldt CEM., Murcia M., Bustamante M., Bonas-Guarch S., Hougaard DM., Mercader JM., Linneberg A., Schraut KE., Lind PA., Medland SE., Shields BM., Knight BA., Chai J-F., Panoutsopoulou K., Bartels M., Sánchez F., Stokholm J., Torrents D., Vinding RK., Willems SM., Atalay M., Chawes BL., Kovacs P., Prokopenko I., Tuke MA., Yaghootkar H., Ruth KS., Jones SE., Loh P-R., Murray A., Weedon MN., Tönjes A., Stumvoll M., Michaelsen KF., Eloranta A-M., Lakka TA., van Duijn CM., Kiess W., Körner A., Niinikoski H., Pahkala K., Raitakari OT., Jacobsson B., Zeggini E., Dedoussis GV., Teo Y-Y., Saw S-M., Montgomery GW., Campbell H., Wilson JF., Vrijkotte TGM., Vrijheid M., de Geus EJCN., Hayes MG., Kadarmideen HN., Holm J-C., Beilin LJ., Pennell CE., Heinrich J., Adair LS., Borja JB., Mohlke KL., Eriksson JG., Widén EE., Hattersley AT., Spector TD., Kähönen M., Viikari JS., Lehtimäki T., Boomsma DI., Sebert S., Vollenweider P., Sørensen TIA., Bisgaard H., Bønnelykke K., Murray JC., Melbye M., Nohr EA., Mook-Kanamori DO., Rivadeneira F., Hofman A., Felix JF., Jaddoe VWV., Hansen T., Pisinger C., Vaag AA., Pedersen O., Uitterlinden AG., Järvelin M-R., Power C., Hyppönen E., Scholtens DM., Lowe WL., Davey Smith G., Timpson NJ., Morris AP., Wareham NJ., Hakonarson H., Grant SFA., Frayling TM., Lawlor DA., Njølstad PR., Johansson S., Ong KK., McCarthy MI., Perry JRB., Evans DM., Freathy RM.
Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.