| 1. |
- Felix, Janine F, et al.
(författare)
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Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index.
- 2016
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Ingår i: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 25:2, s. 389-403
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Tidskriftsartikel (refereegranskat)abstract
- A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10(-8)) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10(-10)) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index.
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| 2. |
- Frazier-Wood, Alexis C., et al.
(författare)
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Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses
- 2016
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Ingår i: Nature Genetics. - : Nature Research (part of Springer Nature). - 1061-4036 .- 1546-1718. ; 48, s. 624-
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Tidskriftsartikel (refereegranskat)abstract
- Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (vertical bar(p) over cap vertical bar approximate to 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.
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| 3. |
- Maddock, Jane, et al.
(författare)
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Vitamin D and cognitive function : A Mendelian randomisation study.
- 2017
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- The causal nature of the association between hypovitaminosis D and poor cognitive function in mid- to later-life is uncertain. Using a Mendelian randomisation(MR) approach, we examined the causal relationship between 25(OH)D and cognitive function. Data came from 172,349 participants from 17 cohorts. DHCR7(rs12785878), CYP2R1 rs12794714) and their combined synthesis score were chosen to proxy 25(OH)D. Cognitive tests were standardised into global and memory scores. Analyses were stratified by 25(OH)D tertiles, sex and age. Random effects meta-analyses assessed associations between 25(OH)D and cognitive function. Associations of serum 25(OH)D with global and memory-related cognitive function were non-linear (lower cognitive scores for both low and high 25(OH)D, p curvature ≤ 0.006), with much of the curvature attributed to a single study. DHCR7, CYP2R1, and the synthesis score were associated with small reductions in 25(OH)D per vitamin D-decreasing allele. However, coefficients for associations with global or memory-related cognitive function were non-significant and in opposing directions for DHCR7 and CYP2R1, with no overall association observed for the synthesis score. Coefficients for the synthesis score and global and memory cognition were similar when stratified by 25(OH)D tertiles, sex and age. We found no evidence for serum 25(OH)D concentration as a causal factor for cognitive performance in mid- to later life.
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| 4. |
- Tyrrell, Jessica, et al.
(författare)
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Genetic Evidence for Causal Relationships Between Maternal Obesity-Related Traits and Birth Weight.
- 2016
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Ingår i: JAMA. - : American Medical Association (AMA). - 1538-3598 .- 0098-7484. ; 315:11, s. 1129-40
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Tidskriftsartikel (refereegranskat)abstract
- Neonates born to overweight or obese women are larger and at higher risk of birth complications. Many maternal obesity-related traits are observationally associated with birth weight, but the causal nature of these associations is uncertain.To test for genetic evidence of causal associations of maternal body mass index (BMI) and related traits with birth weight.Mendelian randomization to test whether maternal BMI and obesity-related traits are potentially causally related to offspring birth weight. Data from 30,487 women in 18 studies were analyzed. Participants were of European ancestry from population- or community-based studies in Europe, North America, or Australia and were part of the Early Growth Genetics Consortium. Live, term, singleton offspring born between 1929 and 2013 were included.Genetic scores for BMI, fasting glucose level, type 2 diabetes, systolic blood pressure (SBP), triglyceride level, high-density lipoprotein cholesterol (HDL-C) level, vitamin D status, and adiponectin level.Offspring birth weight from 18 studies.Among the 30,487 newborns the mean birth weight in the various cohorts ranged from 3325 g to 3679 g. The maternal genetic score for BMI was associated with a 2-g (95% CI, 0 to 3 g) higher offspring birth weight per maternal BMI-raising allele (P = .008). The maternal genetic scores for fasting glucose and SBP were also associated with birth weight with effect sizes of 8 g (95% CI, 6 to 10 g) per glucose-raising allele (P = 7 × 10(-14)) and -4 g (95% CI, -6 to -2 g) per SBP-raising allele (P = 1×10(-5)), respectively. A 1-SD ( ≈ 4 points) genetically higher maternal BMI was associated with a 55-g higher offspring birth weight (95% CI, 17 to 93 g). A 1-SD ( ≈ 7.2 mg/dL) genetically higher maternal fasting glucose concentration was associated with 114-g higher offspring birth weight (95% CI, 80 to 147 g). However, a 1-SD ( ≈ 10 mm Hg) genetically higher maternal SBP was associated with a 208-g lower offspring birth weight (95% CI, -394 to -21 g). For BMI and fasting glucose, genetic associations were consistent with the observational associations, but for systolic blood pressure, the genetic and observational associations were in opposite directions.In this mendelian randomization study, genetically elevated maternal BMI and blood glucose levels were potentially causally associated with higher offspring birth weight, whereas genetically elevated maternal SBP was potentially causally related to lower birth weight. If replicated, these findings may have implications for counseling and managing pregnancies to avoid adverse weight-related birth outcomes.
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| 5. |
- Vimaleswaran, Karani S, et al.
(författare)
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Association of vitamin D status with arterial blood pressure and hypertension risk: a mendelian randomisation study.
- 2014
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Ingår i: The lancet. Diabetes & endocrinology. - 2213-8595 .- 2213-8587. ; 2:9, s. 719-29
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Tidskriftsartikel (refereegranskat)abstract
- Background Low plasma 25-hydroxyvitamin D (25[OH]D) concentration is associated with high arterial blood pressure and hypertension risk, but whether this association is causal is unknown. We used a mendelian randomisation approach to test whether 25(OH)D concentration is causally associated with blood pressure and hypertension risk. Methods In this mendelian randomisation study, we generated an allele score (25[OH]D synthesis score) based on variants of genes that affect 25(OH)D synthesis or substrate availability (CYP2R1 and DHCR7), which we used as a proxy for 25(OH)D concentration. We meta-analysed data for up to 108 173 individuals from 35 studies in the D-CarDia collaboration to investigate associations between the allele score and blood pressure measurements. We complemented these analyses with previously published summary statistics from the International Consortium on Blood Pressure (ICBP), the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and the Global Blood Pressure Genetics (Global BPGen) consortium. Findings In phenotypic analyses (up to n=49 363), increased 25(OH)D concentration was associated with decreased systolic blood pressure (β per 10% increase, −0·12 mm Hg, 95% CI −0·20 to −0·04; p=0·003) and reduced odds of hypertension (odds ratio [OR] 0·98, 95% CI 0·97–0·99; p=0·0003), but not with decreased diastolic blood pressure (β per 10% increase, −0·02 mm Hg, −0·08 to 0·03; p=0·37). In meta-analyses in which we combined data from D-CarDia and the ICBP (n=146 581, after exclusion of overlapping studies), each 25(OH)D-increasing allele of the synthesis score was associated with a change of −0·10 mm Hg in systolic blood pressure (−0·21 to −0·0001; p=0·0498) and a change of −0·08 mm Hg in diastolic blood pressure (−0·15 to −0·02; p=0·01). When D-CarDia and consortia data for hypertension were meta-analysed together (n=142 255), the synthesis score was associated with a reduced odds of hypertension (OR per allele, 0·98, 0·96–0·99; p=0·001). In instrumental variable analysis, each 10% increase in genetically instrumented 25(OH)D concentration was associated with a change of −0·29 mm Hg in diastolic blood pressure (−0·52 to −0·07; p=0·01), a change of −0·37 mm Hg in systolic blood pressure (−0·73 to 0·003; p=0·052), and an 8·1% decreased odds of hypertension (OR 0·92, 0·87–0·97; p=0·002). Interpretation Increased plasma concentrations of 25(OH)D might reduce the risk of hypertension. This finding warrants further investigation in an independent, similarly powered study.
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