Ulla Sovio

Genome-wide association analysis of metabolic traits in a birth cohort from a founder population.

Genome-wide association studies (GWAS) of longitudinal birth cohorts enable joint investigation of environmental and genetic influences on complex traits. We report GWAS results for nine quantitative metabolic traits (triglycerides, high-density lipoprotein, low-density lipoprotein, glucose, insulin, C-reactive protein, body mass index, and systolic and diastolic blood pressure) in the Northern Finland Birth Cohort 1966 (NFBC1966), drawn from the most genetically isolated Finnish regions. We replicate most previously reported associations for these traits and identify nine new associations, several of which highlight genes with metabolic functions: high-density lipoprotein with NR1H3 (LXRA), low-density lipoprotein with AR and FADS1-FADS2, glucose with MTNR1B, and insulin with PANK1. Two of these new associations emerged after adjustment of results for body mass index. Gene–environment interaction analyses suggested additional associations, which will require validation in larger samples. The currently identified loci, together with quantified environmental exposures, explain little of the trait variation in NFBC1966. The association observed between low-density lipoprotein and an infrequent variant in AR suggests the potential of such a cohort for identifying associations with both common, low-impact and rarer, high-impact quantitative trait loci.

Infant vitamin D supplementation and allergic conditions in adulthood: Northern Finland Birth Cohort 1966

Abstract: Allergen‐induced secretion of Th2‐type cytokines and IgE production have recently been reported to be increased in mice treated with 1,25(OH)2D, the active form of vitamin D. Our objective was to investigate whether vitamin D supplementation in infancy is associated with the risk of atopy, allergic rhinitis, and asthma. The Northern Finland Birth Cohort consists of all individuals in the two most northern provinces of Finland who were due to be born in 1966. Data on vitamin D supplementation during the first year of life was obtained in 1967. Current asthma and allergic rhinitis were reported at age 31 years (n= 7,648), and atopy determined by skin‐prick test in a sub‐sample still living in northern Finland or the Helsinki area (n= 5,007). The prevalence of atopy and allergic rhinitis at age 31 years was higher in participants who had received vitamin D supplementation regularly during the first year compared to others (OR 1.46, 95%CI 1.4‐2.0, and OR 1.66, 95%CI 1.1‐1.6, respectively). A similar association was observed for asthma (OR 1.35, 95%CI 0.99‐1.8). These associations persisted after adjustment for a wide range of behavioral and social factors (adjusted: OR 1.33 for all, P= 0.01 for atopy, P= 0.001 for allergic rhinitis, and P= 0.08 for asthma). We observed an association between vitamin D supplementation in infancy and an increased risk of atopy and allergic rhinitis later in life. Further study is required to determine whether these observations reflect long‐term effects on immune regulation or differences in unmeasured determinants of vitamin D supplementation.

A polymorphism within the G6PC2 gene is associated with fasting plasma glucose levels

Several studies have shown that healthy individuals with fasting plasma glucose (FPG) levels at the high end of the normal range have an increased risk of mortality. To identify genetic determinants that contribute to interindividual variation in FPG, we tested 392,935 single-nucleotide polymorphisms (SNPs) in 654 normoglycemic participants for association with FPG, and we replicated the most strongly associated SNP (rs560887, P = 4 × 10–7) in 9353 participants. SNP rs560887 maps to intron 3 of the G6PC2 gene, which encodes glucose-6-phosphatase catalytic subunit–related protein (also known as IGRP), a protein selectively expressed in pancreatic islets. This SNP was associated with FPG (linear regression coefficient β = –0.06 millimoles per liter per A allele, combined P = 4 × 10–23) and with pancreatic β cell function (Homa-B model, combined P = 3 × 10–13) in three populations; however, it was not associated with type 2 diabetes risk. We speculate that G6PC2 regulates FPG by modulating the set point for glucose-stimulated insulin secretion in pancreatic β cells.

Genetic Determinants of Height Growth Assessed Longitudinally from Infancy to Adulthood in the Northern Finland Birth Cohort 1966

Recent genome-wide association (GWA) studies have identified dozens of common variants associated with adult height. However, it is unknown how these variants influence height growth during childhood. We derived peak height velocity in infancy (PHV1) and puberty (PHV2) and timing of pubertal height growth spurt from parametric growth curves fitted to longitudinal height growth data to test their association with known height variants. The study consisted of N = 3,538 singletons from the prospective Northern Finland Birth Cohort 1966 with genotype data and frequent height measurements (on average 20 measurements per person) from 0–20 years. Twenty-six of the 48 variants tested associated with adult height (p<0.05, adjusted for sex and principal components) in this sample, all in the same direction as in previous GWA scans. Seven SNPs in or near the genes HHIP, DLEU7, UQCC, SF3B4/SV2A, LCORL, and HIST1H1D associated with PHV1 and five SNPs in or near SOCS2, SF3B4/SV2A, C17orf67, CABLES1, and DOT1L with PHV2 (p<0.05). We formally tested variants for interaction with age (infancy versus puberty) and found biologically meaningful evidence for an age-dependent effect for the SNP in SOCS2 (p = 0.0030) and for the SNP in HHIP (p = 0.045). We did not have similar prior evidence for the association between height variants and timing of pubertal height growth spurt as we had for PHVs, and none of the associations were statistically significant after correction for multiple testing. The fact that in this sample, less than half of the variants associated with adult height had a measurable effect on PHV1 or PHV2 is likely to reflect limited power to detect these associations in this dataset. Our study is the first genetic association analysis on longitudinal height growth in a prospective cohort from birth to adulthood and gives grounding for future research on the genetic regulation of human height during different periods of growth.

Size at birth, weight gain over the life course, and low-grade inflammation in young adulthood: northern Finland 1966 Birth Cohort study.

AIMS Low-grade inflammation might mediate associations between size at birth, early life growth, excessive weight gain, and subsequent risk of cardiovascular disease in adult life. Our aim was to investigate relationships between fetal growth, weight over the life course, and low-grade inflammation measured by serum high sensitivity C-reactive protein (CRP) levels at 31 years. METHODS AND RESULTS General population-based northern Finland 1966 Birth Cohort study of 5840 participants attending a clinical examination at 31 years, including measurement of CRP. Weight and height were assessed at birth, 12 months, and 14 and 31 years of age. CRP levels at 31 years were 16% [95% confidence interval (CI) 8, 23] higher per 1 kg lower birth weight, 21% (95% CI 2, 37) higher per 10 cm lower birth length, and 24% (95% CI 10, 36) higher per 1 kg/m3 lower ponderal index, after adjustment for potential confounders. Participants with highest tertile body mass index (BMI) at 31 years and lowest tertile birth weight had the highest average CRP levels. Per unit increase in BMI from 14 to 31 years was associated with 16% (95% CI 14, 17) higher CRP levels; the association was larger for those in the top BMI tertile at age 14 years. CONCLUSION Systemic low-grade inflammation may lie on the causal pathway that relates impaired fetal growth and weight gain from childhood to adulthood to adverse adult cardiovascular health. Lifestyle changes from early life might be an important step in reducing cardiovascular risk in adults.

Maternal weight gain during the first half of pregnancy and offspring obesity at 16 years: a prospective cohort study.

Please cite this paper as: Laitinen J, Jääskeläinen A, Hartikainen A, Sovio U, Vääräsmäki M, Pouta A, Kaakinen M, Järvelin M. Maternal weight gain during the first half of pregnancy and offspring obesity at 16 years: a prospective cohort study. BJOG 2012;119:716–723.

Distinct Variants at LIN28B Influence Growth in Height from Birth to Adulthood

We have studied the largely unknown genetic underpinnings of height growth by using a unique resource of longitudinal childhood height data available in Finnish population cohorts. After applying GWAS mapping of potential genes influencing pubertal height growth followed by further characterization of the genetic effects on complete postnatal growth trajectories, we have identified strong association between variants near LIN28B and pubertal growth (rs7759938; female p = 4.0 x 10(-9), male p = 1.5 x 10(-4), combined p = 5.0 x 10(-11), n = 5038). Analysis of growth during early puberty confirmed an effect on the timing of the growth spurt. Correlated SNPs have previously been implicated as influencing both adult stature and age at menarche, the same alleles associating with taller height and later age of menarche in other studies as with later pubertal growth here. Additionally, a partially correlated LIN28B SNP, rs314277, has been associated previously with final height. Testing both rs7759938 and rs314277 (pairwise r(2) = 0.29) for independent effects on postnatal growth in 8903 subjects indicated that the pubertal timing-associated marker rs7759938 affects prepubertal growth in females (p = 7 x 10(-5)) and final height in males (p = 5 x 10(-4)), whereas rs314277 has sex-specific effects on growth (p for interaction = 0.005) that were distinct from those observed at rs7759938. In conclusion, partially correlated variants at LIN28B tag distinctive, complex, and sex-specific height-growth-regulating effects, influencing the entire period of postnatal growth. These findings imply a critical role for LIN28B in the regulation of human growth.

Maternal weight gain during the first half of pregnancy and offspring obesity at 16 years: a prospective cohort study

Please cite this paper as: Laitinen J, Jääskeläinen A, Hartikainen A, Sovio U, Vääräsmäki M, Pouta A, Kaakinen M, Järvelin M. Maternal weight gain during the first half of pregnancy and offspring obesity at 16 years: a prospective cohort study. BJOG 2012;119:716–723.

Genome-wide association study reveals multiple loci associated with primary tooth development during infancy.

Tooth development is a highly heritable process which relates to other growth and developmental processes, and which interacts with the development of the entire craniofacial complex. Abnormalities of tooth development are common, with tooth agenesis being the most common developmental anomaly in humans. We performed a genome-wide association study of time to first tooth eruption and number of teeth at one year in 4,564 individuals from the 1966 Northern Finland Birth Cohort (NFBC1966) and 1,518 individuals from the Avon Longitudinal Study of Parents and Children (ALSPAC). We identified 5 loci at P<5×10−8, and 5 with suggestive association (P<5×10−6). The loci included several genes with links to tooth and other organ development (KCNJ2, EDA, HOXB2, RAD51L1, IGF2BP1, HMGA2, MSRB3). Genes at four of the identified loci are implicated in the development of cancer. A variant within the HOXB gene cluster associated with occlusion defects requiring orthodontic treatment by age 31 years.

Cloninger’s Temperament Dimensions, Socio-economic and Lifestyle Factors and Metabolic Syndrome Markers at Age 31 Years in the Northern Finland Birth Cohort 1966

The aim of this study was to assess the association between temperament and metabolic syndrome markers. Cloninger’s Temperament and Character Inventory and clinical examination were carried out in 1997 in the Northern Finland Birth Cohort 1966 (N = 4364 respondents). Novelty seeking was positively associated with waist circumference in both genders. Systolic blood pressure was highest in men with high harm avoidance and low persistence scores and lowest in women with high reward dependence and high persistence scores. Childhood socio-economic status did not confound these associations. Smoking and alcohol consumption were associated with higher novelty seeking. Our results suggest that temperament is associated with metabolic syndrome markers and this association may be partly mediated by lifestyle factors and socio-economic status in adulthood.