Parent-offspring Trios Research Articles

On Genome-wide Association Studies for Family-Based Designs: An Integrative Analysis Approach Combining Ascertained Family Samples with Unselected Controls

Large numbers of control individuals with genome-wide genotype data are now available through various databases. These controls are regularly used in case-control genome-wide association studies (GWAS) to increase the statistical power. Controls are often "unselected" for the disease of interest and are not matched to cases in terms of confounding factors, making the studies more vulnerable to confounding as a result of population stratification. In this communication, we demonstrate that family-based designs can integrate unselected controls from other studies into the analysis without compromising the robustness of family-based designs against genetic confounding. The result is a hybrid case-control family-based analysis that achieves higher power levels than population-based studies with the same number of cases and controls. This strategy is widely applicable and works ideally for all situations in which both family and case-control data are available. The approach consists of three steps. First, we perform a standard family-based association test that does not utilize the between-family component. Second, we use the between-family information in conjunction with the genotypes from unselected controls in a Cochran-Armitage trend test. The p values from this step are then calculated by rank ordering the individual Cochran-Armitage trend test statistics for the genotype markers. Third, we generate a combined p value with the association p values from the first two steps. Simulation studies are used to assess the achievable power levels of this method compared to standard analysis approaches. We illustrate the approach by an application to a GWAS of attention deficit hyperactivity disorder parent-offspring trios and publicly available controls.

Polymorphisms of the macrophage migration inhibitory factor gene in a UK population with Type 1 diabetes mellitus

Macrophage migration inhibitory factor (MIF) is a potent pro-inflammatory cytokine whose production is transcriptionally regulated by glucose. Experimental data from both Type 1 diabetes mellitus (T1D) patients and animal models suggests a role for MIF in the development of T1D. The aim of this study was to employ gene resequencing to identify common DNA polymorphisms in the MIF gene and subsequently assess haplotype tagged single nucleotide polymorphisms (htSNPs) using a combination of case-control and family-based association analyses in order to assess the association of MIF htSNPs with the development of T1D in a white population. All exons, introns and approximately 3 kb upstream and downstream of the MIF gene were screened for DNA polymorphisms in 46 individuals using DNA sequencing. Genotyping of the htSNPs was performed in 432 cases, 407 control subjects and 290 T1D parent-offspring trios, using Taqman, Sequenom, Pyrosequencing and fluorescence-based microsatellite technologies. Twenty-three polymorphisms (two novel) with a minor allele frequency > 10% were identified. Four MIF htSNPs (rs875643 G>A, rs7388067 C>T, rs5844572 -/CATT, rs6003941 T>G) were identified. Allele and haplotype frequencies were similar between case and control groups (P > 0.6 by permutation test) and assessment of allele transmission distortion from informative parents to affected offspring also failed to find an association. Stratification of these analyses for age-at-onset and human leukocyte antigen (HLA)-DR risk group (DR3/DR4) did not reveal any significant associations. It is unlikely that common polymorphisms in the MIF gene strongly influence susceptibility to T1D in the UK population.

A reappraisal of the association between Dysbindin (DTNBP1) and schizophrenia in a large combined case–control and family-based sample of German ancestry

BackgroundDysbindin (DTNBP1) is a widely studied candidate gene for schizophrenia (SCZ); however, inconsistent results across studies triggered skepticism towards the validity of the findings. In this HapMap-based study, we reappraised the association between Dysbindin and SCZ in a large sample of German ethnicity. MethodSix hundred thirty-four cases with DSM-IV SCZ, 776 controls, and 180 parent–offspring trios were genotyped for 38 Dysbindin SNPs. We also studied two phenotypically-defined subsamples: 147 patients with a positive family history of SCZ (FH-SCZ+) and SCZ patients characterized for cognitive performance with Trail-Making Tests A and B (TMT-A: n=219; TMT-B: n=247). Given previous evidence of gene–gene interactions in SCZ involving the COMT gene, we also assessed epistatic interactions between Dysbindin markers and 14 SNPs in COMT. ResultsNo association was detected between Dysbindin markers and SCZ, or in the FH-SCZ+ subgroup. Only one marker (rs1047631, previously reported to be part of a risk haplotype), showed a nominally significant association with performance on TMT-A and TMT-B; these findings did not remain significant after correction for multiple comparisons. Similarly, no pair-wise epistatic interactions between Dysbindin and COMT markers remained significant after correction for 504 pair-wise comparisons. ConclusionsOur results, based on one of the largest samples of European Caucasians and using narrowly-defined criteria for SCZ, do not support the etiological involvement of Dysbindin markers in SCZ. Larger samples may be needed in order to unravel Dysbindin's possible role in the genetic basis of proposed intermediate phenotypes of SCZ or to detect epistatic interactions.

Genome-Wide Association Studies of Family Data in Pharmacogenetics: A Case Study

Genome-wide associations studies (GWAS) have become routine in human genetics research; however the application of GWAS to pharmacogenomics research is just beginning. As these studies make their way into pharmacogenetics, there are several considerations specific to pharmacogenetics that should be made. In this manuscript, we discuss these considerations and provide concrete examples with GWAS data for an asthma clinical trial using parent-offspring trios.

ATRIUM: Testing Untyped SNPs in Case-Control Association Studies with Related Individuals

In genome-wide association studies, only a subset of all genomic variants are typed by current, high-throughput, SNP-genotyping platforms. However, many of the untyped variants can be well predicted from typed variants, with linkage disequilibrium (LD) information among typed and untyped variants available from an external reference panel such as HapMap. Incorporation of such external information can allow one to perform tests of association between untyped variants and phenotype, thereby making more efficient use of the available genotype data. When related individuals are included in case-control samples, the dependence among their genotypes must be properly addressed for valid association testing. In the context of testing untyped variants, an additional analytical challenge is that the dependence, across related individuals, of the partial information on untyped-SNP genotypes must also be assessed and incorporated into the analysis for valid inference. We address this challenge with ATRIUM, a method for case-control association testing with untyped SNPs, based on genome screen data in samples in which some individuals are related. ATRIUM uses LD information from an external reference panel to specify a one-degree-of-freedom test of association with an untyped SNP. It properly accounts for dependence in the partial information on untyped-SNP genotypes across related individuals. We demonstrate that ATRIUM is robust in that it maintains the nominal type I error rate even when the external reference panel is not well matched to the case-control sample. We apply the method to detect association between type 2 diabetes and variants on chromosome 10 in the Framingham SHARe data.

Nicotinic Acetylcholine Receptor α4 Subunit Gene Variation Associated with Attention Deficit Hyperactivity Disorder

Previous pharmacological, human genetics, and animal models have implicated the nicotinic acetylcholine receptor α4 subunit (CHRNA4) gene in the pathogenesis of attention deficit/hyperactivity disorder (ADHD). The objective of this study is to examine the genetic association between single nucleotide polymorphisms in the CHRNA4 gene (rs2273502, rs1044396, rs1044397, and rs3827020 loci) and ADHD. Both case-control and family-based designs are used. Children aged 6 to 16 years were interviewed and assessed with the children behavior checklist and the revised conner' parent rating scale to identify probands. No significant differences in the frequency distribution of genotypes or alleles were found between the case and control groups. However, further haplotype analyses showed the CCGG haplotype on risk for ADHD in 164 case-control samples and the standard transmission disequilibrium test analyses suggest that the allele C of rs2273502 was over-transferred in 98 ADHD parent-offspring trios. These findings suggest that the CHRNA4 gene may play a role in the pathogenesis of ADHD.

Copy number variation at 1q21.1 associated with neuroblastoma

Common copy number variations (CNVs) represent a significant source of genetic diversity, yet their influence on phenotypic variability, including disease susceptibility, remains poorly understood. To address this problem in human cancer, we performed a genome-wide association study of CNVs in the childhood cancer neuroblastoma, a disease in which single nucleotide polymorphism variations are known to influence susceptibility. We first genotyped 846 Caucasian neuroblastoma patients and 803 healthy Caucasian controls at approximately 550,000 single nucleotide polymorphisms, and performed a CNV-based test for association. We then replicated significant observations in two independent sample sets comprised of a total of 595 cases and 3,357 controls. Here we describe the identification of a common CNV at chromosome 1q21.1 associated with neuroblastoma in the discovery set, which was confirmed in both replication sets. This CNV was validated by quantitative polymerase chain reaction, fluorescent in situ hybridization and analysis of matched tumour specimens, and was shown to be heritable in an independent set of 713 cancer-free parent-offspring trios. We identified a previously unknown transcript within the CNV that showed high sequence similarity to several neuroblastoma breakpoint family (NBPF) genes and represents a new member of this gene family (NBPF23). This transcript was preferentially expressed in fetal brain and fetal sympathetic nervous tissues, and the expression level was strictly correlated with CNV state in neuroblastoma cells. These data demonstrate that inherited copy number variation at 1q21.1 is associated with neuroblastoma and implicate a previously unknown neuroblastoma breakpoint family gene in early tumorigenesis of this childhood cancer.

IL1B polymorphisms modulate cystic fibrosis lung disease

Variability in pulmonary disease severity is found in patients with cystic fibrosis (CF) who have identical mutations in the CF transmembrane conductance regulator (CFTR) gene. We hypothesized that one factor accounting for heterogeneity in pulmonary disease severity is variation in the family of genes affecting the biology of interleukin-1 (IL-1), which impacts acquisition and maintenance of Pseudomonas aeruginosa infection in animal models of chronic infection. We genotyped 58 single nucleotide polymorphisms (SNPs) in the IL-1 gene cluster in 808 CF subjects from the University of North Carolina and Case Western Reserve University (UNC/CWRU) joint cohort. All were homozygous for DeltaF508, and categories of "severe" (cases) or "mild" (control subjects) lung disease were defined by the lowest or highest quartile of forced expired volume (FEV(1)) for age in the CF population. After adjustment for age and gender, genotypic data were tested for association with lung disease severity. Odds ratios (ORs) comparing severe versus mild CF were also calculated for each genotype (with the homozygote major allele as the reference group) for all 58 SNPs. From these analyses, nine SNPs with a moderate effect size, OR < or =0.5 or >1.5, were selected for further testing. To replicate the case-control study results, we genotyped the same nine SNPs in a second population of CF parent-offspring trios (recruited from Children's Hospital Boston), in which the offspring had similar pulmonary phenotypes. For the trio analysis, both family-based and population-based associations were performed. SNPs rs1143634 and rs1143639 in the IL1B gene demonstrated a consistent association with lung disease severity categories (P < 0.10) and longitudinal analysis of lung disease severity (P < 0.10) in CF in both the case-control and family-based studies. In females, there was a consistent association (false discovery rate adjusted joint P-value <0.06 for both SNPs) in both the analysis of lung disease severity in the UNC/CWRU cohort and the family-based analysis of affection status. Our findings suggest that IL1beta is a clinically relevant modulator of CF lung disease.

Detection of disease-associated deletions in case–control studies using SNP genotypes with application to rheumatoid arthritis

Genomic deletions have long been known to play a causative role in microdeletion syndromes. Recent whole-genome genetic studies have shown that deletions can increase the risk for several psychiatric disorders, suggesting that genomic deletions play an important role in the genetic basis of complex traits. However, the association between genomic deletions and common, complex diseases has not yet been systematically investigated in gene mapping studies. Likelihood-based statistical methods for identifying disease-associated deletions have recently been developed for familial studies of parent-offspring trios. The purpose of this study is to develop statistical approaches for detecting genomic deletions associated with complex disease in case-control studies. Our methods are designed to be used with dense single nucleotide polymorphism (SNP) genotypes to detect deletions in large-scale or whole-genome genetic studies. As more and more SNP genotype data for genome-wide association studies become available, development of sophisticated statistical approaches will be needed that use these data. Our proposed statistical methods are designed to be used in SNP-by-SNP analyses and in cluster analyses based on combined evidence from multiple SNPs. We found that these methods are useful for detecting disease-associated deletions and are robust in the presence of linkage disequilibrium using simulated SNP data sets. Furthermore, we applied the proposed statistical methods to SNP genotype data of chromosome 6p for 868 rheumatoid arthritis patients and 1,197 controls from the North American Rheumatoid Arthritis Consortium. We detected disease-associated deletions within the region of human leukocyte antigen in which genomic deletions were previously discovered in rheumatoid arthritis patients.

Positive selection of a CD36 nonsense variant in sub-Saharan Africa, but no association with severe malaria phenotypes

The prevalence of CD36 deficiency in East Asian and African populations suggests that the causal variants are under selection by severe malaria. Previous analysis of data from the International HapMap Project indicated that a CD36 haplotype bearing a nonsense mutation (T1264G; rs3211938) had undergone recent positive selection in the Yoruba of Nigeria. To investigate the global distribution of this putative selection event, we genotyped T1264G in 3420 individuals from 66 populations. We confirmed the high frequency of 1264G in the Yoruba (26%). However, the 1264G allele is less common in other African populations and absent from all non-African populations without recent African admixture. Using long-range linkage disequilibrium, we studied two West African groups in depth. Evidence for recent positive selection at the locus was demonstrable in the Yoruba, although not in Gambians. We screened 70 variants from across CD36 for an association with severe malaria phenotypes, employing a case–control study of 1350 subjects and a family study of 1288 parent–offspring trios. No marker was significantly associated with severe malaria. We focused on T1264G, genotyping 10 922 samples from four African populations. The nonsense allele was not associated with severe malaria (pooled allelic odds ratio 1.0; 95% confidence interval 0.89–1.12; P = 0.98). These results suggest a range of possible explanations including the existence of alternative selection pressures on CD36, co-evolution between host and parasite or confounding caused by allelic heterogeneity of CD36 deficiency.

A family-based study of the IL3RA gene on susceptibility to schizophrenia in a Chinese Han population

Schizophrenia has been observed to be associated with various abnormalities in cytokines and cytokine receptors that have been one of the recent focal points of immunological research in schizophrenia. Recent reports have showed that IL-3 gene, colony stimulating factor 2 receptor alpha (CSF2RA) and IL-3 receptor alpha (IL3RA) are associated with schizophrenia. The aim of this study was to investigate IL3RA gene variants in schizophrenia among a Chinese population by using a family-based association approach. Our sample included 101 Chinese parent–offspring trios of Han descent. All subjects were genotype for IL3RA-rs6603272 and -rs6645249 using PCR techniques. Single marker analysis showed a significant association for rs6603272 (X2=5.15, df=1, P=0.023), but not for the rs6645249. However, there was a significant genotypic association of both the polymorphisms with schizophrenia (for rs6603272, X2=6.15, df=2, P=0.046; for rs6645249, X2=21.79, df=2, P=1.85e-005). Haplotype TDT was statistically significant (X2=5.14, df=1, P=0.023), with the rs6603272(T)–rs6645249(G) haplotype significantly associated with schizophrenia (OR=1.66; 95% CI=1.08–2.55). In conclusion, our family-based association study also revealed a small but significant contribution of the IL3RA variants to susceptibility to schizophrenia in a Chinese population.

A Unified Approach to Genotype Imputation and Haplotype-Phase Inference for Large Data Sets of Trios and Unrelated Individuals

We present methods for imputing data for ungenotyped markers and for inferring haplotype phase in large data sets of unrelated individuals and parent-offspring trios. Our methods make use of known haplotype phase when it is available, and our methods are computationally efficient so that the full information in large reference panels with thousands of individuals is utilized. We demonstrate that substantial gains in imputation accuracy accrue with increasingly large reference panel sizes, particularly when imputing low-frequency variants, and that unphased reference panels can provide highly accurate genotype imputation. We place our methodology in a unified framework that enables the simultaneous use of unphased and phased data from trios and unrelated individuals in a single analysis. For unrelated individuals, our imputation methods produce well-calibrated posterior genotype probabilities and highly accurate allele-frequency estimates. For trios, our haplotype-inference method is four orders of magnitude faster than the gold-standard PHASE program and has excellent accuracy. Our methods enable genotype imputation to be performed with unphased trio or unrelated reference panels, thus accounting for haplotype-phase uncertainty in the reference panel. We present a useful measure of imputation accuracy, allelic R(2), and show that this measure can be estimated accurately from posterior genotype probabilities. Our methods are implemented in version 3.0 of the BEAGLE software package.

Design and Clinical Characteristics of a Homogeneous Schizophrenia Pedigree Sample from Tamil Nadu, India

The genetic complexity of schizophrenia may be compounded by the diagnostic imprecision inherent in distinguishing schizophrenia from closely related mood and substance use disorders. Further complexity may arise from studying genetically and/or environmentally diverse ethnic groups. Reported here are the ascertainment, demographic features and clinical characteristics, of a diagnostically and ethnically homogeneous schizophrenia pedigree sample from Tamil Nadu, India. Also reported is the theoretical power to detect genetic linkage in the subset of affected sibling pairs. Affected sibling pair and trio pedigrees were identified by caste/ethnicity. Affected probands and siblings fulfilled DSM-IV criteria for schizophrenia or schizoaffective disorder. The present sample consisted of 159 affected sibling pairs and 187 parent-offspring trios originating primarily from the Tamil Brahmin caste, but also incorporating pedigrees from genetically similar, geographically proximal caste groups. Consistent with previous studies in Tamil Nadu, a very low prevalence of affective psychoses such as schizoaffective disorder, was observed, with most affected individuals having schizophrenia (499/504). Also observed were extremely low rates of nicotine (12.4%), alcohol (1.1%) and illicit drug use (0%). Most affected individuals exhibited negative symptoms (>90%) and a severe, chronic course. All participants lived in the same geographic and climatic region and most affected individuals resided with close family members, increasing uniformity of the sociocultural environment. In affected sibling pairs, power to detect linkage to small-effect risk loci was modest, but this homogeneous sample may be enriched for loci of larger effect. This Indian schizophrenia sample exhibits diagnostic and ethnic homogeneity with high consistency of sociocultural environmental features. These characteristics should assist efforts to identify risk genes for schizophrenia.

P01-14 Nicotinic acetylcholine receptor α4 subunit gene variation associated with chinese han patients with attention deficit hyperactivity disorder

Previous pharmacological, human genetical, and animal models have implicated the nicotinic acetylcholine receptor α4 subunit (CHRNA4) gene in the pathogenesis of ADHD. The objective of this study is to examine genetic association between single nucleotide polymorphisms (SNPs) in the CHRNA4 gene (rs2273502, rs1044396, rs1044397 and rs3827020 loci) and ADHD. Both case-control and family-based design were used in this study. Children aged 6 to 16 years were interviewed and assessed with the CBCL and CPRS-R to identify probands. No significant differences in frequency distribution of genotypes or alleles between the case and control groups were found. However, further haplotype analyses showed CCGG haplotype on risk for ADHD in 164 case-control sample and TDT analysis suggested that the allele C of rs2273502 over-transferred in 98 ADHD parent-offspring trios. Our findings suggest that CHRNA4 gene may play a role in the pathogenesis of ADHD, and further work is necessary to replicate and confirm what role the CHRNA4 gene may play in the etiology and pathogenesis of ADHD in large independent samples.

Genome‐wide association scan of the time to onset of attention deficit hyperactivity disorder

A time-to-onset analysis for family-based samples was performed on the genomewide association (GWAS) data for attention deficit hyperactivity disorder (ADHD) to determine if associations exist with the age at onset of ADHD. The initial dataset consisted of 958 parent-offspring trios that were genotyped on the Perlegen 600,000 SNP array. After data cleaning procedures, 429,981 autosomal SNPs and 930 parent-offspring trios were used found suitable for use and a family-based logrank analysis was performed using that age at first ADHD symptoms as the quantitative trait of interest. No SNP achieved genome-wide significance, and the lowest P-values had a magnitude of 10(-7). Several SNPs among a pre-specified list of candidate genes had nominal associations including SLC9A9, DRD1, ADRB2, SLC6A3, NFIL3, ADRB1, SYT1, HTR2A, ARRB2, and CHRNA4. Of these findings SLC9A9 stood out as a promising candidate, with nominally significant SNPs in six distinct regions of the gene.

Support for Neuregulin 1 as a Susceptibility Gene for Bipolar Disorder and Schizophrenia

There is support that Neuregulin 1 (NRG1) plays a role in susceptibility to schizophrenia but limited evidence for its involvement in bipolar disorder. We wished to investigate further the involvement of NRG1 in schizophrenia and bipolar disorder. We used hierarchical association analysis in parent-offspring trios, 634 with schizophrenia/schizoaffective disorder (SZ/SA) and 243 with bipolar 1 disorder (BP1). The primary analysis was the markers defining the "core Icelandic haplotype" (HAP(ICE)). We undertook polymorphism discovery, additional genotyping, and also explored phenotypic associations, as a secondary analysis aimed at refining the signal. The initial global haplotype test yielded significant evidence for association (p = .01) with SZ/SA and BP1 (p = .004), although HAP(ICE) was not overtransmitted. The marker showing strongest evidence for association in the deCODE studies, SNP8NRG221533, was associated with SZ/SA (p(corrected) = .039) and with BP1 (p(corrected) = .039), with BP1 showing association to the opposite allele as SZ/SA. The pattern of transmission at SNP8NRG221533 was significantly different in SZ/SA than in BP1 (p = .0004). Secondary analyses of markers and phenotypes provided no additional evidence for association to SZ/SA. However, a new marker, rs7014762, was associated with an a priori defined "typical" bipolar phenotype characterized by excellent recovery between episodes and no mood incongruent features (p(corrected) = .003). Our data provide significant levels of support for NRG1 as a susceptibility gene for both major forms of psychosis, and this cannot be interpreted as being due to population stratification. More tentatively, they also might indicate the presence of multiple alleles that influence the psychosis phenotype.

Evaluation of HapMap data in six populations of European descent

We studied how well the European CEU samples used in the Haplotype Mapping Project (HapMap) represent five European populations by analyzing nuclear family samples from the Swedish, Finnish, Dutch, British and Australian (European ancestry) populations. The number of samples from each population (about 30 parent-offspring trios) was similar to that in the HapMap sample sets. A panel of 186 single nucleotide polymorphisms (SNPs) distributed over the 1.5 Mb region of the GRID2 gene on chromosome 4 was genotyped. The genotype data were compared pair-wise between the HapMap sample and the other population samples. Principal component analysis (PCA) was used to cluster the data from different populations with respect to allele frequencies and to define the markers responsible for observed variance. The only sample with detectable differences in allele frequencies was that from Kuusamo, Finland. This sample also separated from the others, including the other Finnish sample, in the PCA analysis. A set of tagSNPs was defined based on the HapMap data and applied to the samples. The tagSNPs were found to capture the genetic variation in the analyzed region at r(2)>0.8 at levels ranging from 95% in the Kuusamo sample to 87% in the Australian sample. To capture the maximal genetic variation in the region, the Kuusamo, HapMap and Australian samples required 58, 63 and 73 native tagSNPs, respectively. The HapMap CEU sample represents the European samples well for tagSNP selection, with some caution regarding estimation of allele frequencies in the Finnish Kuusamo sample, and a slight reduction in tagging efficiency in the Australian sample.

A genome-wide association study in 574 schizophrenia trios using DNA pooling

The cost of genome-wide association (GWA) studies can be prohibitively high when large samples are genotyped. We conducted a GWA study on schizophrenia (SZ) and to reduce the cost, we used DNA pooling. We used a parent-offspring trios design to avoid the potential problems of population stratification. We constructed pools from 605 unaffected controls, 574 SZ patients and a third pool from all the parents of the patients. We hybridized each pool eight times on Illumina HumanHap550 arrays. We estimated the allele frequencies of each pool from the averaged intensities of the arrays. The significance level of results in the trios sample was estimated on the basis of the allele frequencies in cases and non-transmitted pseudocontrols, taking into account the technical variability of the data. We selected the highest ranked SNPs for individual genotyping, after excluding poorly performing SNPs and those that showed a trend in the opposite direction in the control pool. We genotyped 63 SNPs in 574 trios and analysed the results with the transmission disequilibrium test. Forty of those were significant at P<0.05, with the best result at P=1.2 x 10(-6) for rs11064768. This SNP is within the gene CCDC60, a coiled-coil domain gene. The third best SNP (P=0.00016) is rs893703, within RBP1, a candidate gene for schizophrenia.

Exploring the developmental overnutrition hypothesis using parental-offspring associations and FTO as an instrumental variable.

BackgroundThe developmental overnutrition hypothesis suggests that greater maternal obesity during pregnancy results in increased offspring adiposity in later life. If true, this would result in the obesity epidemic progressing across generations irrespective of environmental or genetic changes. It is therefore important to robustly test this hypothesis.Methods and FindingsWe explored this hypothesis by comparing the associations of maternal and paternal pre-pregnancy body mass index (BMI) with offspring dual energy X-ray absorptiometry (DXA)–determined fat mass measured at 9 to 11 y (4,091 parent–offspring trios) and by using maternal FTO genotype, controlling for offspring FTO genotype, as an instrument for maternal adiposity. Both maternal and paternal BMI were positively associated with offspring fat mass, but the maternal association effect size was larger than that in the paternal association in all models: mean difference in offspring sex- and age-standardised fat mass z-score per 1 standard deviation BMI 0.24 (95% confidence interval [CI]: 0.22 to 0.26) for maternal BMI versus 0.13 (95% CI: 0.11, 0.15) for paternal BMI; p-value for difference in effect < 0.001. The stronger maternal association was robust to sensitivity analyses assuming levels of non-paternity up to 20%. When maternal FTO, controlling for offspring FTO, was used as an instrument for the effect of maternal adiposity, the mean difference in offspring fat mass z-score per 1 standard deviation maternal BMI was −0.08 (95% CI: −0.56 to 0.41), with no strong statistical evidence that this differed from the observational ordinary least squares analyses (p = 0.17).ConclusionsNeither our parental comparisons nor the use of FTO genotype as an instrumental variable, suggest that greater maternal BMI during offspring development has a marked effect on offspring fat mass at age 9–11 y. Developmental overnutrition related to greater maternal BMI is unlikely to have driven the recent obesity epidemic.

Substantial intergenerational increases in body mass index are not explained by the fetal overnutrition hypothesis: the Cardiovascular Risk in Young Finns Study

Background: According to the fetal overnutrition hypothesis, intrauterine influences of maternal obesity increased lifelong obesity risk in the offspring. If the hypothesis is true, then the association between maternal body mass index (BMI; in kg/m2) and offspring BMI should be stronger than the association between paternal BMI and offspring BMI, because only the mother directly influences the fetal environment.Objectives: We prospectively examined intergenerational change in BMI and tested the fetal overnutrition hypothesis.Design: Data on offspring weight were obtained from mothers. BMI was assessed from 2980 complete parent-offspring trios when the offspring were 3 to 18 y of age. The assessment of offspring BMI was repeated 21 y later at age 24–39 y.Results: Adult BMI of the offspring was 1.21 units higher than the BMI of their parents at the same age, which indicates an increase in obesity levels across generations (P < 0.0001). Maternal BMI was more strongly associated with offspring birth weight than was paternal BMI (P = 0.0009). However, there were no such differences in parent-offspring associations for BMI at later developmental stages when offspring were aged 3-39 y (P > 0.35). The results did not materially change in a sensitivity analysis for 1% to 15% nonpaternity.Conclusions: Because offspring share all genes with their parents, the observed substantially higher adult BMI for offspring than for parents is likely explained by environmental influences. No support was found for any specific influence from fetal environment on this intergenerational increase in adult obesity. The findings were consistent with the fetal overnutrition hypothesis only in relation to birth weight.