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Genome-wide associations for birth weight and correlations with adult disease.

ABSTRACT: Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P?

SUBMITTER: Horikoshi M

PROVIDER: S-EPMC5164934 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Genome-wide associations for birth weight and correlations with adult disease.

Horikoshi Momoko M Beaumont Robin N RN Day Felix R FR Warrington Nicole M NM Kooijman Marjolein N MN Fernandez-Tajes Juan J Feenstra Bjarke B van Zuydam Natalie R NR Gaulton Kyle J KJ Grarup Niels N Bradfield Jonathan P JP Strachan David P DP Li-Gao Ruifang R Ahluwalia Tarunveer S TS Kreiner Eskil E Rueedi Rico R Lyytikäinen Leo-Pekka LP Cousminer Diana L DL Wu Ying Y Thiering Elisabeth E Wang Carol A CA Have Christian T CT Hottenga Jouke-Jan JJ Vilor-Tejedor Natalia N Joshi Peter K PK Boh Eileen Tai Hui ETH Ntalla Ioanna I Pitkänen Niina N Mahajan Anubha A van Leeuwen Elisabeth M EM Joro Raimo R Lagou Vasiliki V Nodzenski Michael M Diver Louise A LA Zondervan Krina T KT Bustamante Mariona M Marques-Vidal Pedro P Mercader Josep M JM Bennett Amanda J AJ Rahmioglu Nilufer N Nyholt Dale R DR Ma Ronald Ching Wan RCW Tam Claudia Ha Ting CHT Tam Wing Hung WH Ganesh Santhi K SK van Rooij Frank Ja FJ Jones Samuel E SE Loh Po-Ru PR Ruth Katherine S KS Tuke Marcus A MA Tyrrell Jessica J Wood Andrew R AR Yaghootkar Hanieh H Scholtens Denise M DM Paternoster Lavinia L Prokopenko Inga I Kovacs Peter P Atalay Mustafa M Willems Sara M SM Panoutsopoulou Kalliope K Wang Xu X Carstensen Lisbeth L Geller Frank F Schraut Katharina E KE Murcia Mario M van Beijsterveldt Catharina Em CE Willemsen Gonneke G Appel Emil V R EVR Fonvig Cilius E CE Trier Caecilie C Tiesler Carla Mt CM Standl Marie M Kutalik Zoltán Z Bonas-Guarch Sílvia S Hougaard David M DM Sánchez Friman F Torrents David D Waage Johannes J Hollegaard Mads V MV de Haan Hugoline G HG Rosendaal Frits R FR Medina-Gomez Carolina C Ring Susan M SM Hemani Gibran G McMahon George G Robertson Neil R NR Groves Christopher J CJ Langenberg Claudia C Luan Jian'an J Scott Robert A RA Zhao Jing Hua JH Mentch Frank D FD MacKenzie Scott M SM Reynolds Rebecca M RM Lowe William L WL Tönjes Anke A Stumvoll Michael M Lindi Virpi V Lakka Timo A TA van Duijn Cornelia M CM Kiess Wieland W Körner Antje A Sørensen Thorkild Ia TI Niinikoski Harri H Pahkala Katja K Raitakari Olli T OT Zeggini Eleftheria E Dedoussis George V GV Teo Yik-Ying YY Saw Seang-Mei SM Melbye Mads M Campbell Harry H Wilson James F JF Vrijheid Martine M de Geus Eco Jcn EJ Boomsma Dorret I DI Kadarmideen Haja N HN Holm Jens-Christian JC Holm Jens-Christian JC Hansen Torben T Sebert Sylvain S Hattersley Andrew T AT Beilin Lawrence J LJ Newnham John P JP Newnham John P JP Pennell Craig E CE Heinrich Joachim J Adair Linda S LS Borja Judith B JB Mohlke Karen L KL Eriksson Johan G JG Widén Elisabeth E EE Kähönen Mika M Viikari Jorma S JS Lehtimäki Terho T Vollenweider Peter P Vollenweider Peter P Bønnelykke Klaus K Bisgaard Hans H Mook-Kanamori Dennis O DO Hofman Albert A Rivadeneira Fernando F Uitterlinden André G AG Pisinger Charlotta C Pisinger Charlotta C Pedersen Oluf O Power Christine C Hyppönen Elina E Wareham Nicholas J NJ Hakonarson Hakon H Davies Eleanor E Walker Brian R BR Jaddoe Vincent Wv VW Jarvelin Marjo-Riitta MR Grant Struan Fa SF Vaag Allan A AA Lawlor Debbie A DA Frayling Timothy M TM Frayling Timothy M TM Davey Smith George G Morris Andrew P AP Ong Ken K KK Felix Janine F JF Timpson Nicholas J NJ Perry John Rb JR Evans David M DM McCarthy Mark I MI McCarthy Mark I MI Freathy Rachel M RM

Nature 20160928 7624

Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where f ...[more]

PMID: 27680694

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Project description:ObjectivePrior studies have shown that there is an inverse association between birth weight and stroke in adulthood; however, whether such association is causal remains yet known and those studies cannot distinguish between the direct fetal effect and the indirect maternal effect. The aim of the study is to untangle such relationship using novel statistical genetic approaches.MethodsWe first utilized linkage disequilibrium score regression (LDSC) and Genetic analysis incorporating Pleiotropy and Annotation (GPA) to estimate the overall genetic correlation between birth weight and stroke. Then, with a set of valid birth-weight instruments which had adjusted fetal and maternal effects, we performed a two-sample Mendelian randomization (MR) to evaluate its causal effect on stroke based summary statistics from large scale genome-wide association study (GWAS) (n = 264,498 for birth weight and 446,696 for stroke). We further validated the MR results with extensive sensitivity analyses.ResultsBoth LDSC and GPA demonstrated significant evidence of shared maternal genetic foundation between birth weight and stroke, with the genetic correlation estimated to -0.176. However, no fetal genetic correlation between birth weight and stroke was detected. Furthermore, the inverse variance weighted MR demonstrated the maternally causal effect of birth weight on stroke was 1.12 (95% confidence interval [CI] 1.00-1.27). The maternal ORs of birth weight on three subtypes of stroke including cardioembolic stroke (CES), large artery stroke (LAS) and small vessel stroke (SVS) were 1.16 (95% CI 0.93-1.43), 1.50 (95% CI 1.14-1.96) and 1.47 (95% CI 1.15-1.87), respectively. In contrast, no fetal causal associations were found between birth weight and stroke or the subtypes. Those results were robust against extensive sensitivity analyses, with Egger regression ruling out the possibility of pleiotropy and multivariable MR excluding the likelihood of confounding or mediation effects of other risk factors of stroke.ConclusionThis study provides empirically supportive evidence on the fetal developmental origins of stroke and its subtypes. However, further investigation is warranted to understand the pathophysiological role of low birth weight in developing stroke.

Project description:BackgroundBirth weight (BW) predicts many health outcomes, but the relative contributions of genes and environmental factors to BW remain uncertain. Some studies report stronger mother-offspring than father-offspring BW correlations, with attenuated father-offspring BW correlations when the mother is stunted. These findings have been interpreted as evidence that maternal genetic or environmental factors play an important role in determining birth size, with small maternal size constraining paternal genetic contributions to offspring BW. Here we evaluate mother-offspring and father-offspring birth weight (BW) associations and evaluate whether maternal stunting constrains genetic contributions to offspring birth size.Methods/principal findingsData include BW of offspring (n?=?1,101) born to female members (n?=?382) and spouses of male members (n?=?275) of a birth cohort (born 1983-84) in Metropolitan Cebu, Philippines. Regression was used to relate parental and offspring BW adjusting for confounders. Resampling testing was used to evaluate whether false paternity could explain any evidence for excess matrilineal inheritance. In a pooled model adjusting for maternal height and confounders, parental BW was a borderline-significantly stronger predictor of offspring BW in mothers compared to fathers (sex of parent interaction p?=?0.068). In separate multivariate models, each kg in mother's and father's BW predicted a 271±53 g (p<0.00001) and 132±55 g (p?=?0.017) increase in offspring BW, respectively. Resampling statistics suggested that false paternity rates of >25% and likely 50% would be needed to explain these differences. There was no interaction between maternal stature and maternal BW (interaction p?=?0.520) or paternal BW (p?=?0.545).Conclusions/significanceEach kg change in mother's BW predicted twice the change in offspring BW as predicted by a change in father's BW, consistent with an intergenerational maternal effect on offspring BW. Evidence for excess matrilineal BW heritability at all levels of maternal stature points to indirect genetic, mitochondrial, or epigenetic maternal contributions to offspring fetal growth.

Project description:Selection for larger litter size has increased the number of low individual birth weight (BWi) pigs and produced sows with a repeatable low average litter birth weight phenotype (BWP). Using an average of 3.6 litters records per sow, BWP was established in 644 nucleus-multiplication sows producing replacement gilts in a large commercial operation and classified as low (L-BWP, <1.18 kg, n = 85), medium (M-BWP, ≥1.18 to ≤1.35 kg, n = 250), or high (H-BWP, >1.35 kg, n = 309) on the basis of a BWi of 1.18 kg below which there was a high risk of early mortality and the average BWi (1.35 kg) for the population. In subsequent litters, potential replacement gilts born to these sows (n = 7,341) received a unique identification tag that allowed the impact of BWi, BWP, and their interactions on the efficiency of replacement gilt production to be evaluated. Negative effects of BWi on mortality until day 4 after birth were confirmed (P < 0.05) and cumulative losses to weaning, to day 70 of age, and to final pre-selection at 165 d of age were affected (P ≤ 0.05) by the interaction between BWP and BWi. Among the 2,035 gilts for which records for selection efficiency and production to fourth parity were available, a lower BWi decreased the probability of gilts reaching pubertal estrus (P < 0.05) after 21 and 28 d of boar stimulation starting at 180 d of age, with no effect of BWP. Overall, neither BWi, BWP, nor their interaction affected age at puberty. After breeding, only the main effect of BWP affected productivity and retention in the sow herd. In parities 1 and 2, percent stillborn was higher in litters born to gilts from H-BWP compared with L-BWP dams (P < 0.05), and in parity 2, total born and born alive were lower in sows derived from H-BWP compared with other BWPs. There were no differences in retention based on BWP classes until parity 2, after which retention tended (P ≤ 0.09) to be lower in sows derived from H-BWP compared with L-BWP dams. These results provide evidence that sow BWP is an important factor in the overall efficiency of replacement gilt management. This study also confirms that effective gilt selection and pre-breeding management protocols support excellent sow lifetime productivity and mitigate the risk of a high BWP in the litter of origin affecting retention in the breeding herd.

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Genome-wide associations for birth weight and correlations with adult disease.

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Genome-wide associations for birth weight and correlations with adult disease.

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