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1.  IgA measurements in over 12 000 Swedish twins reveal sex differential heritability and regulatory locus near CD30L 
Human Molecular Genetics  2014;23(15):4177-4184.
In a broad attempt to improve the understanding of the genetic regulation of serum IgA levels, the heritability was estimated in over 12 000 Swedish twins, and a genome-wide association study was conducted in a subsample of 9617. Using the classical twin model the heritability was found to be significantly larger among females (61%) compared with males (21%), while contribution from shared environment (20%) was only seen for males. By modeling the genetic relationship matrix with IgA levels, we estimate that a substantial proportion (31%) of variance in IgA levels can ultimately be explained by the investigated SNPs. The genome-wide association study revealed significant association to two loci: (i) rs6928791 located on chromosome 6, 22 kb upstream of the gene SAM and SH3 domain containing 1 (SASH1) and (ii) rs13300483 on chromosome 9, situated 12 kb downstream the CD30 ligand (CD30L) encoding gene. The association to rs13300483 was replicated in two additional independent Swedish materials. The heritability of IgA levels is moderate and can partly be attributable to common variation in the CD30L locus.
PMCID: PMC4082371  PMID: 24676358
4.  Web-Based Self-Reported Height, Weight, and Body Mass Index Among Swedish Adolescents: A Validation Study 
Web-collected height and weight are increasingly used in epidemiological studies; however, the validity has rarely been evaluated.
The aim of the study was to validate self-reported height, weight, and corresponding body mass index (BMI) among Swedish adolescents aged approximately 16 years. A secondary aim was to investigate possible prediction factors for validity of self-reported BMI.
The study included 1698 adolescents from the population-based cohort BAMSE. Height and weight were collected through a Web-based questionnaire and subsequently measured using standard procedures. Differences between reported and measured height, weight, and corresponding BMI were compared by t tests and agreement was evaluated by Pearson correlation and Bland-Altman plots. Multivariable linear regression analysis was used to investigate whether lifestyle and demographic factors predicted validity of self-reported BMI.
On average, weight was underestimated by 1.1 kg and height was overestimated by 0.5 cm, leading to an underestimation of BMI by 0.5 kg/m2. Correlation coefficients were .98 for height, .97 for weight, and .94 for BMI, and highly significant. Females underestimated weight to a higher extent than males and overweight and obese participants underestimated weight to a higher extent than normal-weight participants, which resulted in higher underestimation of BMI. Underweight participants, on the contrary, overestimated weight and correspondingly BMI. Overall, a high proportion of participants were classified into the correct BMI category; however, among overweight and obese participants, only 60.2% (139/231) and 46% (20/44) were correctly classified, respectively. In the multivariable prediction model, only gender and BMI status significantly predicted discrepancy between reported and measured BMI.
Web-collected BMI may be used as a valid, quick, and cost-effective alternative to measured BMI among Swedish adolescents. The accuracy of self-reported BMI declines with increasing BMI and self-reported BMI should not be used to estimate the prevalence of overweight or obesity.
PMCID: PMC4382564  PMID: 25791395
adolescent; body height; body weight; body mass index; validity; Internet
5.  Body Mass Index Development from Birth to Early Adolescence; Effect of Perinatal Characteristics and Maternal Migration Background in a Swedish Cohort 
PLoS ONE  2014;9(10):e109519.
Well documented diversity in risk of developing overweight and obesity between children of immigrant and of native mothers, might be explained by different body mass index (BMI) development trajectories in relation to maternal and perinatal characteristics of offspring.
To assess BMI development trajectories among children born to immigrant and to Swedish mothers from birth to adolescence in relation to perinatal characteristics.
A cohort of 2517 children born in Stockholm during 1994 to 1996 was followed with repeated measurement of height and weight at eleven time points until age 12 years. We estimated changes over time for BMI in relation to maternal and perinatal characteristics of offspring using mixed linear model analysis for repeated measure data.
We observed a significant BMI change over time in children and time interaction with maternal migration status (P<0.0001). Estimated BMI over time adjusted for maternal and perinatal characteristics of offspring, showed slower BMI growth before age of 5, followed by an earlier plateau and steeper BMI growth after 5 years among children of immigrant mothers compared with children of Swedish mothers. These differences in BMI growth were more prominent among children with mothers from outside Europe.
Beside reinforcing early childhood as a crucial period in development of overweight, the observed slower BMI development at early childhood among children of immigrants followed by a steeper increase in BMI compared with children of Swedish mothers is important for further studies and for planning of preventive public health programs.
PMCID: PMC4193784  PMID: 25303283
6.  A novel common variant in DCST2 is associated with length in early life and height in adulthood 
van der Valk, Ralf J.P. | Kreiner-Møller, Eskil | Kooijman, Marjolein N. | Guxens, Mònica | Stergiakouli, Evangelia | Sääf, Annika | Bradfield, Jonathan P. | Geller, Frank | Hayes, M. Geoffrey | Cousminer, Diana L. | Körner, Antje | Thiering, Elisabeth | Curtin, John A. | Myhre, Ronny | Huikari, Ville | Joro, Raimo | Kerkhof, Marjan | Warrington, Nicole M. | Pitkänen, Niina | Ntalla, Ioanna | Horikoshi, Momoko | Veijola, Riitta | Freathy, Rachel M. | Teo, Yik-Ying | Barton, Sheila J. | Evans, David M. | Kemp, John P. | St Pourcain, Beate | Ring, Susan M. | Davey Smith, George | Bergström, Anna | Kull, Inger | Hakonarson, Hakon | Mentch, Frank D. | Bisgaard, Hans | Chawes, Bo | Stokholm, Jakob | Waage, Johannes | Eriksen, Patrick | Sevelsted, Astrid | Melbye, Mads | van Duijn, Cornelia M. | Medina-Gomez, Carolina | Hofman, Albert | de Jongste, Johan C. | Taal, H. Rob | Uitterlinden, André G. | Armstrong, Loren L. | Eriksson, Johan | Palotie, Aarno | Bustamante, Mariona | Estivill, Xavier | Gonzalez, Juan R. | Llop, Sabrina | Kiess, Wieland | Mahajan, Anubha | Flexeder, Claudia | Tiesler, Carla M.T. | Murray, Clare S. | Simpson, Angela | Magnus, Per | Sengpiel, Verena | Hartikainen, Anna-Liisa | Keinanen-Kiukaanniemi, Sirkka | Lewin, Alexandra | Da Silva Couto Alves, Alexessander | Blakemore, Alexandra I. | Buxton, Jessica L. | Kaakinen, Marika | Rodriguez, Alina | Sebert, Sylvain | Vaarasmaki, Marja | Lakka, Timo | Lindi, Virpi | Gehring, Ulrike | Postma, Dirkje S. | Ang, Wei | Newnham, John P. | Lyytikäinen, Leo-Pekka | Pahkala, Katja | Raitakari, Olli T. | Panoutsopoulou, Kalliope | Zeggini, Eleftheria | Boomsma, Dorret I. | Groen-Blokhuis, Maria | Ilonen, Jorma | Franke, Lude | Hirschhorn, Joel N. | Pers, Tune H. | Liang, Liming | Huang, Jinyan | Hocher, Berthold | Knip, Mikael | Saw, Seang-Mei | Holloway, John W. | Melén, Erik | Grant, Struan F.A. | Feenstra, Bjarke | Lowe, William L. | Widén, Elisabeth | Sergeyev, Elena | Grallert, Harald | Custovic, Adnan | Jacobsson, Bo | Jarvelin, Marjo-Riitta | Atalay, Mustafa | Koppelman, Gerard H. | Pennell, Craig E. | Niinikoski, Harri | Dedoussis, George V. | Mccarthy, Mark I. | Frayling, Timothy M. | Sunyer, Jordi | Timpson, Nicholas J. | Rivadeneira, Fernando | Bønnelykke, Klaus | Jaddoe, Vincent W.V.
Human Molecular Genetics  2014;24(4):1155-1168.
Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 × 10−6) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; β = 0.046, SE = 0.008, P = 2.46 × 10−8, explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 × 10−4) and adult height (N = 127 513; P = 1.45 × 10−5). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.
PMCID: PMC4447786  PMID: 25281659
7.  Effect of Parental Migration Background on Childhood Nutrition, Physical Activity, and Body Mass Index 
Journal of Obesity  2014;2014:406529.
Background. Poor nutrition, lack of physical activity, and obesity in children have important public health implications but, to date, their effects have not been studied in the growing population of children in Sweden with immigrant parents. Methods. We estimated the association between parental migration background and nutrition, physical activity, and weight in 8-year-old children born in Stockholm between 1994 and 1996 of immigrants and Swedish parents (n = 2589). Data were collected through clinical examination and questionnaires filled out by parents. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using multivariable logistic regression. Results. Children of immigrants complied more closely with Nordic Nutrition Recommendations compared with those of Swedes (OR = 1.35, 95% CI 1.11–1.64). They had higher intake of dietary fibre, vitamins C, B6, and E, folic acid, and polyunsaturated fatty acids (omega-3 and omega-6) reflecting higher consumption of foods of plant origin, but lower intake of vitamins A and D, calcium, and iron reflecting lower consumption of dairy products. Children of immigrants had higher intake of sucrose reflecting higher consumption of sugar and sweets. Furthermore, these children had a higher risk of having low physical activity (OR = 1.31, 95% CI 1.06–1.62) and being overweight (OR = 1.33, 95% CI 1.06–1.65) compared with children of Swedish parents. The odds of having low physical activity and being overweight were even higher in children whose parents were both immigrants. A low level of parental education was associated with increased risk of low physical activity regardless of immigration background. Conclusions. Culturally appropriate tools to capture the diverse range of ethnic foods and other lifestyle habits are needed. Healthcare professionals should be aware of the low levels of physical activity, increased weight, and lack of consumption of some important vitamins among children of immigrants.
PMCID: PMC4058807  PMID: 24991430
8.  Genome-wide association study of body mass index in 23,000 individuals with and without asthma 
Both asthma and obesity are complex disorders that are influenced by environmental and genetic factors. Shared genetic factors between asthma and obesity have been proposed to partly explain epidemiological findings of co-morbidity between these conditions.
To identify genetic variants that are associated with body mass index (BMI) in asthmatic children and adults, and to evaluate if there are differences between the genetics of BMI in asthmatics and healthy individuals.
In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23,000 individuals with predominantly European descent, of whom 8,165 are asthmatics.
We report associations between several DENND1B variants (p=2.2×10−7 for rs4915551) on chromosome 1q31 and BMI from a meta-analysis of GWAS data using 2,691 asthmatic children (screening data). The top DENND1B SNPs were next evaluated in seven independent replication data sets comprising 2,014 asthmatics, and rs4915551 was nominally replicated (p<0.05) in two of the seven studies and of borderline significance in one (p=0.059). However, strong evidence of effect heterogeneity was observed and overall, the association between rs4915551 and BMI was not significant in the total replication data set, p=0.71. Using a random effects model, BMI was overall estimated to increase by 0.30 kg/m2 (p=0.01 for combined screening and replication data sets, N=4,705) per additional G allele of this DENND1B SNP. FTO was confirmed as an important gene for adult and childhood BMI regardless of asthma status.
Conclusions and Clinical Relevance
DENND1B was recently identified as an asthma susceptibility gene in a GWAS on children, and here we find evidence that DENND1B variants may also be associated with BMI in asthmatic children. However, the association was overall not replicated in the independent data sets and the heterogeneous effect of DENND1B points to complex associations with the studied diseases that deserve further study.
PMCID: PMC3608930  PMID: 23517042
Association; Asthma; BMI; Genetics; Genome-wide; Obesity
9.  Does Pet Ownership in Infancy Lead to Asthma or Allergy at School Age? Pooled Analysis of Individual Participant Data from 11 European Birth Cohorts 
PLoS ONE  2012;7(8):e43214.
To examine the associations between pet keeping in early childhood and asthma and allergies in children aged 6–10 years.
Pooled analysis of individual participant data of 11 prospective European birth cohorts that recruited a total of over 22,000 children in the 1990s.
Exposure definition
Ownership of only cats, dogs, birds, rodents, or cats/dogs combined during the first 2 years of life.
Outcome definition
Current asthma (primary outcome), allergic asthma, allergic rhinitis and allergic sensitization during 6–10 years of age.
Data synthesis
Three-step approach: (i) Common definition of outcome and exposure variables across cohorts; (ii) calculation of adjusted effect estimates for each cohort; (iii) pooling of effect estimates by using random effects meta-analysis models.
We found no association between furry and feathered pet keeping early in life and asthma in school age. For example, the odds ratio for asthma comparing cat ownership with “no pets” (10 studies, 11489 participants) was 1.00 (95% confidence interval 0.78 to 1.28) (I2 = 9%; p = 0.36). The odds ratio for asthma comparing dog ownership with “no pets” (9 studies, 11433 participants) was 0.77 (0.58 to 1.03) (I2 = 0%, p = 0.89). Owning both cat(s) and dog(s) compared to “no pets” resulted in an odds ratio of 1.04 (0.59 to 1.84) (I2 = 33%, p = 0.18). Similarly, for allergic asthma and for allergic rhinitis we did not find associations regarding any type of pet ownership early in life. However, we found some evidence for an association between ownership of furry pets during the first 2 years of life and reduced likelihood of becoming sensitized to aero-allergens.
Pet ownership in early life did not appear to either increase or reduce the risk of asthma or allergic rhinitis symptoms in children aged 6–10. Advice from health care practitioners to avoid or to specifically acquire pets for primary prevention of asthma or allergic rhinitis in children should not be given.
PMCID: PMC3430634  PMID: 22952649
10.  MMP12, Lung Function, and COPD in High-Risk Populations 
The New England journal of medicine  2009;361(27):2599-2608.
Genetic variants influencing lung function in children and adults may ultimately lead to the development of chronic obstructive pulmonary disease (COPD), particularly in high-risk groups.
We tested for an association between single-nucleotide polymorphisms (SNPs) in the gene encoding matrix metalloproteinase 12 (MMP12) and a measure of lung function (prebronchodilator forced expiratory volume in 1 second [FEV1]) in more than 8300 subjects in seven cohorts that included children and adults. Within the Normative Aging Study (NAS), a cohort of initially healthy adult men, we tested for an association between SNPs that were associated with FEV1 and the time to the onset of COPD. We then examined the relationship between MMP12 SNPs and COPD in two cohorts of adults with COPD or at risk for COPD.
The minor allele (G) of a functional variant in the promoter region of MMP12 (rs2276109 [−82A→G]) was positively associated with FEV1 in a combined analysis of children with asthma and adult former and current smokers in all cohorts (P=2×10−6). This allele was also associated with a reduced risk of the onset of COPD in the NAS cohort (hazard ratio, 0.65; 95% confidence interval [CI], 0.46 to 0.92; P = 0.02) and with a reduced risk of COPD in a cohort of smokers (odds ratio, 0.63; 95% CI, 0.45 to 0.88; P = 0.005) and among participants in a family-based study of early-onset COPD (P = 0.006).
The minor allele of a SNP in MMP12 (rs2276109) is associated with a positive effect on lung function in children with asthma and in adults who smoke. This allele is also associated with a reduced risk of COPD in adult smokers.
PMCID: PMC2904064  PMID: 20018959

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