Maternal and offspring fasting glucose and type 2 diabetes-associated genetic variants and cognitive function at age 8: a Mendelian randomization study in the Avon Longitudinal Study of Parents and Children

BMC Medical Genetics

Sarah J Lewis¹  George Davey Smith²  Susan M Ring¹  David Gunnell¹  Andrew R Ness³  Yoav Ben–Shlomo¹  Debbie A Lawlor²  Carolina Bonilla¹ 

[1] School of Social and Community Medicine, University of Bristol, Bristol, BS8 2BN, United Kingdom;MRC Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom;School of Oral and Dental Sciences, University of Bristol, Bristol, United Kingdom

关键词: ALSPAC;    IQ;    Type 2 diabetes;    Fasting glucose;    Mendelian randomization;   

Others  :  1177792
DOI  :  10.1186/1471-2350-13-90

 received in 2012-02-16, accepted in 2012-09-20,  发布年份 2012

【 摘 要 】

Background

In observational epidemiological studies type 2 diabetes (T2D) and both low and high plasma concentrations of fasting glucose have been found to be associated with lower cognitive performance. These associations could be explained by confounding.

Methods

In this study we looked at the association between genetic variants, known to be robustly associated with fasting glucose and T2D risk, in the mother and her offspring to determine whether there is likely to be a causal link between early life exposure to glucose and child’s intelligence quotient (IQ) scores in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. We generated a fasting glucose (FGGRS) and a T2D (T2DGRS) genetic risk score and used them in a Mendelian randomization approach.

Results

We found a strong correlation between the FGGRS and fasting glucose plasma measurements that were available for a subset of children, but no association of either the maternal or the offspring FGGRS with child’s IQ was observed. In contrast, the maternal T2DGRS was positively associated with offspring IQ.

Conclusions

Maternal and offspring genetic variants which are associated with glucose levels are not associated with offspring IQ, suggesting that there is unlikely to be a causal link between glucose exposure in utero and IQ in childhood. Further exploration in even larger cohorts is required to exclude the possibility that our null findings were due to a lack of statistical power.

【 授权许可】

   
2012 Bonilla et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Benton D: Vitamins and neural and cognitive developmental outcomes in children. Proc Nutr Soc 2012, 71:14-26.
• [2]Georgieff MK: Nutrition and the developing brain: nutrient priorities and measurement. Am J Clin Nutr 2007, 85:614S-620S.
• [3]Donohoe RT, Benton D: Cognitive functioning is susceptible to the level of blood glucose. Psychopharmacology 1999, 145:378-385.
• [4]Craft S, Newcomer J, Kanne S, et al.: Memory improvement following induced hyperinsulinemia in Alzheimer’s disease. Neurobiol Aging 1996, 17:123-130.
• [5]Baumann MU, Deborde S, Illsley NP: Placental glucose transfer and fetal growth. Endocrine 2002, 19:13-22.
• [6]Gaither K, Quraishi AN, Illsley NP: Diabetes alters the expression and activity of the human placental GLUT1 glucose transporter. J Clin Endocrinol Metab 1999, 84:695-701.
• [7]Ornoy A, Wolf A, Ratzon N, Greenbaum C, Dulitzky M: Neurodevelopmental outcome at early school age of children born to mothers with gestational diabetes. Arch Dis Child Fetal Neonatal Ed 1999, 81:F10-F14.
• [8]Yamashita Y, Kawano Y, Kuriya N, et al.: Intellectual development of offspring of diabetic mothers. Acta Paediatr 1996, 85:1192-1196.
• [9]Dahlquist G, Källén B: School marks for Swedish children whose mothers had diabetes during pregnancy: a population-based study. Diabetologia 2007, 50:1826-1831.
• [10]Benton D, Owens DS, Parker PY: Blood glucose influences memory and attention in young adults. Neuropsychologia 1994, 32:595-607.
• [11]Benton D, Parker PY: Breakfast, blood glucose, and cognition. Am J Clin Nutr 1998, 67:772S-778S.
• [12]Cukierman T, Gerstein HC, Williamson JD: Cognitive decline and dementia in diabetes–systematic overview of prospective observational studies. Diabetologia 2005, 48:2460-2469.
• [13]Yaffe K, Blackwell T, Kanaya AM, et al.: Diabetes, impaired fasting glucose, and development of cognitive impairment in older women. Neurology 2004, 63:658-663.
• [14]Ott A, Stolk R, van Harskamp F, et al.: Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology 1999, 53:1937-1997.
• [15]Awad N, Gagnon M, Messier C: The relationship between impaired glucose tolerance, type 2 diabetes, and cognitive function. J Clin Exp Neuropsychol 2004, 26:1044-1080.
• [16]Davey Smith G: Use of genetic markers and gene-diet interactions for interrogating population-level causal influences of diet on health. Genes Nutr 2011, 6:27-43.
• [17]Davey Smith G, Ebrahim S: “Mendelian randomization”: can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol 2003, 32:1-22.
• [18]Dupuis J, Langenberg C, Prokopenko I, et al.: New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet 2010, 42:105-116.
• [19]Zeggini E, Weedon MN, Lindgren CM, et al.: Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 2007, 316:1336-1341.
• [20]Zeggini E, Scott LJ, Saxena R, et al.: Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat Genet 2008, 40:638-645.
• [21]Barker A, Sharp SJ, Timpson NJ, et al.: Association of genetic loci with glucose levels in childhood and adolescence: a meta-analysis of over 6,000 children. Diabetes 2011, 60:1805-1812.
• [22]Saxena R, Elbers CC, Guo Y, et al.: Large-scale gene-centric meta-analysis across 39 studies identifies Type 2 diabetes loci. Am J Hum Genet 2012, 90:410-425.
• [23]Boyd A, Golding J, Macleod J, et al.: Cohort Profile: the “children of the 90s”--the index offspring of the avon longitudinal study of parents and children. Int J Epidemiol 2012.
• [24]Fraser A, Macdonald-Wallis C, Tilling K, et al.: Cohort Profile: the Avon longitudinal study of parents and children: ALSPAC mothers cohort. Int J Epidemiol 2012.
• [25]Joinson C, Heron J, Butler R, et al.: A United Kingdom population-based study of intellectual capacities in children with and without soiling, daytime wetting, and bed-wetting. Pediatrics 2007, 120:e308-316.
• [26]Wechsler D: Manual for the Wechsler Intelligence Scale for Children. 3rd edition. San Antonio: The Psychological Corporation; 1991.
• [27]Shultis WA, Leary SD, Ness AR, et al.: Haemoglobin A1c is not a surrogate for glucose and insulin measures for investigating the early life and childhood determinants of insulin resistance and Type 2 diabetes in healthy children. An analysis from the Avon longitudinal study of parents and chil. Diabet Med 2006, 23:1357-1363.
• [28]Lawlor DA, Fraser A, Lindsay RS, et al.: Association of existing diabetes, gestational diabetes and glycosuria in pregnancy with macrosomia and offspring body mass index, waist and fat mass in later childhood: findings from a prospective pregnancy cohort. Diabetologia 2010, 53:89-97.
• [29]Jones RW, Ring S, Tyfield L, et al.: A new human genetic resource: a DNA bank established as part of the Avon Longitudinal Study of Pregnancy and Childhood (ALSPAC). Eur J Hum Genet 2000, 8:653-660.
• [30]Price AL, Patterson NJ, Plenge RM, et al.: Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 2006, 38:904-909.
• [31]Li Y, Willer CJ, Ding J, Scheet P, Abecasis GR: MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet Epidemiol 2010, 34:816-834.
• [32]Konheim YL, Wolford JK: Association of a promoter variant in the inducible cyclooxygenase-2 gene (PTGS2) with type 2 diabetes mellitus in Pima Indians. Hum Genet 2003, 113:377-381.
• [33]Hivert M-F, Jablonski KA, Perreault L, et al.: Updated genetic score based on 34 confirmed type 2 diabetes loci is associated with diabetes incidence and regression to normoglycemia in the diabetes prevention program. Diabetes 2011, 60:1340-1348.
• [34]Unoki H, Takahashi A, Kawaguchi T, et al.: SNPs in KCNQ1 are associated with susceptibility to type 2 diabetes in East Asian and European populations. Nat Genet 2008, 40:1098-1102.
• [35]World Health Organization: Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia. Geneva, Switzerland: World Health Organization; 2006:1-50.
• [36]World Health Organization: Use of glycated haemoglobin (HbA1c) in the diagnosis of diabetes mellitus. Geneva, Switzerland: World Health Organization; 2011:1-25.
• [37]Cheurfa N, Brenner GM, Reis AF, et al.: Decreased insulin secretion and increased risk of type 2 diabetes associated with allelic variations of the WFS1 gene: the Data from Epidemiological Study on the Insulin Resistance Syndrome (DESIR) prospective study. Diabetologia 2011, 54:554-562.
• [38]Yasuda K, Miyake K, Horikawa Y, et al.: Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus. Nat Genet 2008, 40:1092-1097.
• [39]Soranzo N, Sanna S, Wheeler E, et al.: Common variants at 10 genomic loci influence hemoglobin A1c levels via glycemic and nonglycemic pathways. Diabetes 2010, 59:3229-3239.
• [40]Bouatia-Naji N, Rocheleau G, Van Lommel L, et al.: A polymorphism within the G6PC2 gene is associated with fasting plasma glucose levels. Science 2008, 320:1085-1088.
• [41]Rizzo TA, Metzger BE, Dooley SL, Cho NH: Early malnutrition and child neurobehavioral development: insights from the study of children of diabetic mothers. Child Dev 1997, 68:26-38.
• [42]Fraser A, Nelson SM, Macdonald-Wallis C, Lawlor DA: Associations of existing diabetes, gestational diabetes and glycosuria with offspring IQ and educational attainment: the avon longitudinal study of parents and children. Exp Diabetes Res
• [43]Temple RC, Hardiman M, Pellegrini M, Horrocks L, Martinez-Cengotitabengoa M-T: Cognitive function in 6- to 12-year-old offspring of women with Type 1 diabetes. Diabet Med 2011, 28:845-848.
• [44]Ornoy A, Ratzon N, Greenbaum C, Wolf A, Dulitzky M: School-age children born to diabetic mothers and to mothers with gestational diabetes exhibit a high rate of inattention and fine and gross motor impairment. J Pediatr Endocrinol Metab 2001, 14(Suppl 1):681-689.