A genome-wide linkage scan for body mass index on Framingham Heart Study families

BACKGROUND: Genome-wide scan data from a community-based sample was used to identify the genetic factors that affect body mass index (BMI). BMI was defined as weight (kg) over the square of height (m), where weight and height were obtained from the first measurement available between the ages of 40 and 50 years. RESULTS: Significant familial correlations were observed in mother:father (spouse) relative pairs and in all relative pairs examined except parent:daughter pairs. Single-point sib-pair regression analysis provided nominal evidence for linkage (p < 0.05) of loci to BMI at 23 markers. Multi-point sib-pair regression analysis provided nominal evidence for linkage to BMI at 42 loci on 12 chromosomes. Empirical p-values showed results consistent with the multi-point results; all but three of the loci identified by multi-point analysis were also significant. CONCLUSION: The largest regions of nominally significant linkage were found on chromosomes 2, 3, and 11. The most significant evidence for linkage was obtained with markers D2S1788, D2S1356, D2S1352, D3S1744, and D11S912 from multi-point sib-pair single-trait regression analysis. Our results are in agreement with some of the recently published reports on BMI using various data sets including the Framingham Heart Study data

Developmental outcomes after early surgery for complex congenital heart disease:a systematic review and meta-analysis

AIM: (1) To systematically review the literature on developmental outcomes from infancy to adolescence of children with complex congenital heart disease (CHD) who underwent early surgery; (2) to run a meta-regression analysis on the Bayley Scales of Infant Development, Second Edition Mental Developmental Index and Psychomotor Developmental Index (PDI) of infants up to 24 months and IQs of preschool-aged children to adolescents; (3) to assess associations between perioperative risk factors and outcomes. METHOD: We searched pertinent literature (January 1990 to January 2019) in PubMed, Embase, CINAHL, and PsycINFO. Selection criteria included infants with complex CHD who had primary surgery within the first 9 weeks of life. Methodological quality, including risk of bias and internal validity, were assessed. RESULTS: In total, 185 papers met the inclusion criteria; the 100 with high to moderate methodological quality were analysed in detail. Substantial heterogeneity in the group with CHD and in methodology existed. The outcome of infants with single-ventricle CHD was inferior to those with two-ventricle CHD (respectively: average scores for PDI 77 and 88; intelligence scores 92 and 98). Perioperative risk factors were inconsistently associated with developmental outcomes. INTERPRETATION: The literature on children undergoing surgery in early infancy suggests that infants with a single ventricle are at highest risk of adverse developmental outcomes. WHAT THIS PAPER ADDS: Children with complex congenital heart disease (CHD) are at increased risk of impaired developmental outcome. Children with single-ventricle CHD have worse outcomes than children with two-ventricle CHD. Children with two-ventricle CHD gradually grow out of their initial developmental impairment. Perioperative factors are inconsistently associated with outcome

The Twin Research Registry at SRI International

The Twin Research Registry (TRR) at SRI International is a community-based registry of twins established in 1995 by advertising in local media, mainly on radio stations and in newspapers. As of August 2012, there are 3120 twins enrolled; 86% are 18 or older (mean age 44.9 years, SD 16.9) and 14% less than 18 years of age (mean age 8.9 years, SD 4.5); 67% are female, and 62% are self-reported monozygotic. More than 1375 twins have participated in studies over the last 15 years in collaboration with the University of California Medical Center in San Francisco, the University of Texas MD Anderson Cancer Center, and the Stanford University School of Medicine. Each twin completes a registration form with basic demographic information either online at the TRR website or during a telephone interview. Contact is maintained with members by means of annual newsletters and birthday cards. The managers of the TRR protect the confidentiality of twin data with established policies; no information is given to other researchers without prior permission from the twins and all methods and procedures are reviewed by an Institutional Review Board. Phenotypes studied thus far include those related to nicotine metabolism, mutagen sensitivity, pain response before and after administration of an opioid, and a variety of immunological responses to environmental exposures including second-hand smoke and vaccination for seasonal influenza virus and varicella zoster virus. Twins in the TRR have participated in studies of complex, clinically-relevant phenotypes that would not be feasible to measure in larger samples

The quality of general movements in infants with complex congenital heart disease undergoing surgery in the neonatal period

Background: Advances in diagnostic technologies, surgical management, and perioperative care have increased survival for neonates with complex congenital heart disease (CCHD). The success of these advances exposed a heightened risk of brain injury and developmental disabilities. The General Movements Assessment, a non-invasive method, may detect early neurodevelopmental impairments in high-risk infants. Aims: To examine whether infants with CCHD undergoing neonatal surgery have higher prevalence of atypical general movements (GMs) than a reference group, and whether single ventricle physiology with systemic oxygen saturations <90% increases risk for atypical GMs. Methods: Serial General Movements Assessment (GMA) in a cohort of infants with CCHD (n = 74) at writhing (term-6 weeks) and fidgety (7–17 weeks) GM-age. GMA focused on the presence of definitely abnormal GM-complexity and absent fidgety movements. Single GMAs at 3 months were available from a reference sample of Dutch infants (n = 300). Regression analyses examined relationships between cardiac characteristics and definitely abnormal GM-complexity. Results: Higher prevalence of definitely abnormal GM-complexity in infants with CCHD compared to reference infants (adjusted OR 5.938, 95% CI 2.423–14.355), single ventricle CCHD increased the risk. Occurrence of absent fidgety movements was similar in infants with CCHD and reference infants (adjusted OR 0.475, 95% CI 0.058–3.876). Systemic postoperative oxygen saturations <90% was associated with higher risk of definitely abnormal GM-complexity at fidgety (adjusted OR 16.445 95% CI 1.149–235.281), not at writhing age. Conclusions: Infants with CCHD, especially those with single ventricle CCHD, are at increased risk of definitely abnormal GM-complexity. GMA at fidgety age is recommended

Genomic regions linked to alcohol consumption in the Framingham Heart Study

BACKGROUND: Pedigree, demographic, square-root transformed maximum alcohol (SRMAXAPD) and maximum cigarette (MAXCPD) consumption, and genome-wide scan data from the Framingham Heart Study (FHS) were used to investigate genetic factors that may affect alcohol and cigarette consumption in this population-based sample. RESULTS: A significant sister:sister correlation greater than spouse correlation was observed for MAXCPD only. Single-point sib-pair regression analysis provided nominal evidence for linkage of loci to both SRMAXAPD and MAXCPD consumption traits, with more significant evidence of linkage to SRMAXAPD than to MAXCPD. One genomic region, chr9q21.11, exhibits significant multi-point sib-pair regression to SRMAXAPD. CONCLUSION: SRMAXAPD exhibits greater evidence for genetic linkage than does MAXCPD in the FHS sample. Four regions of the genome exhibiting nominal evidence for linkage to SRMAXAPD in the FHS sample correspond to regions of the genome previously identified as linked to alcoholism or related traits in the family data set ascertained on individuals affected with alcohol dependence known as COGA

Identification of susceptibility loci for complex diseases in a case-control association study using the Genetic Analysis Workshop 14 dataset

Although current methods in genetic epidemiology have been extremely successful in identifying genetic loci responsible for Mendelian traits, most common diseases do not follow simple Mendelian modes of inheritance. It is important to consider how our current methodologies function in the realm of complex diseases. The aim of this study was to determine the ability of conventional association methods to fine map a locus of interest. Six study populations were selected from 10 replicates (New York) from the Genetic Analysis Workshop 14 simulated dataset and analyzed for association between the disease trait and locus D2. Genotypes from 45 single-nucleotide polymorphisms in the telomeric region of chromosome 3 were analyzed by Pearson's chi-square tests for independence to test for association with the disease trait of interest. A significant association was detected within the region; however, it was found 3 cM from the documented location of the D2 disease locus. This result was most likely due to the method used for data simulation. In general, this study showed that conventional case-control association methods could detect disease loci responsible for the development of complex traits

Linkage analysis of the GAW14 simulated dataset with microsatellite and single-nucleotide polymorphism markers in large pedigrees

Recent studies have suggested that a high-density single nucleotide polymorphism (SNP) marker set could provide equivalent or even superior information compared with currently used microsatellite (STR) marker sets for gene mapping by linkage. The focus of this study was to compare results obtained from linkage analyses involving extended pedigrees with STR and single-nucleotide polymorphism (SNP) marker sets. We also wanted to compare the performance of current linkage programs in the presence of high marker density and extended pedigree structures. One replicate of the Genetic Analysis Workshop 14 (GAW14) simulated extended pedigrees (n = 50) from New York City was analyzed to identify the major gene D2. Four marker sets with varying information content and density on chromosome 3 (STR [7.5 cM]; SNP [3 cM, 1 cM, 0.3 cM]) were analyzed to detect two traits, the original affection status, and a redefined trait more closely correlated with D2. Multipoint parametric and nonparametric linkage analyses (NPL) were performed using programs GENEHUNTER, MERLIN, SIMWALK2, and S.A.G.E. SIBPAL. Our results suggested that the densest SNP map (0.3 cM) had the greatest power to detect linkage for the original trait (genetic heterogeneity), with the highest LOD score/NPL score and mapping precision. However, no significant improvement in linkage signals was observed with the densest SNP map compared with STR or SNP-1 cM maps for the redefined affection status (genetic homogeneity), possibly due to the extremely high information contents for all maps. Finally, our results suggested that each linkage program had limitations in handling the large, complex pedigrees as well as a high-density SNP marker set