Association of timing of menarche with depressive symptoms and depression in adolescence: Mendelian randomisation study.
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ABSTRACT:
SUBMITTER: Sequeira ME
PROVIDER: S-EPMC5209630 | biostudies-literature | 2017 Jan
REPOSITORIES: biostudies-literature
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Association of timing of menarche with depressive symptoms and depression in adolescence: Mendelian randomisation study.
Sequeira Maija-Eliina ME Lewis Sarah J SJ Bonilla Carolina C Smith George Davey GD Joinson Carol C
The British journal of psychiatry : the journal of mental science 20160804 1
<h4>Background</h4>Observational studies report associations between early menarche and higher levels of depressive symptoms and depression. However, no studies have investigated whether this association is causal.<h4>Aims</h4>To determine whether earlier menarche is a causal risk factor for depressive symptoms and depression in adolescence.<h4>Method</h4>The associations between a genetic score for age at menarche and depressive symptoms at 14, 17 and 19 years, and depression at 18 years, were ...[more]
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Project description:BackgroundEarlier puberty is widely linked with future obesity and cardiometabolic disease. We examined whether age at puberty onset likely influences adiposity and cardiometabolic traits independent of childhood adiposity.Methods and findingsOne-sample Mendelian randomisation (MR) analyses were conducted on up to 3,611 white-European female and male offspring from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort recruited at birth via mothers between 1 April 1991 and 31 December 1992. Time-sensitive exposures were age at menarche and age at voice breaking. Outcomes measured at age 18 y were body mass index (BMI), dual-energy X-ray absorptiometry-based fat and lean mass indices, blood pressure, and 230 cardiometabolic traits derived from targeted metabolomics (150 concentrations plus 80 ratios from nuclear magnetic resonance [NMR] spectroscopy covering lipoprotein subclasses of cholesterol and triglycerides, amino acids, inflammatory glycoproteins, and others). Adjustment was made for pre-pubertal BMI measured at age 8 y. For negative control MR analyses, BMI and cardiometabolic trait measures taken at age 8 y (before puberty, and which therefore cannot be an outcome of puberty itself) were used. For replication analyses, 2-sample MR was conducted using summary genome-wide association study data on up to 322,154 adults for post-pubertal BMI, 24,925 adults for post-pubertal NMR cardiometabolic traits, and 13,848 children for pre-pubertal obesity (negative control). Like observational estimates, 1-sample MR estimates in ALSPAC using 351 polymorphisms for age at menarche (explaining 10.6% of variance) among 2,053 females suggested that later age at menarche (per year) was associated with -1.38 kg/m2 of BMI at age 18 y (or -0.34 SD units, 95% CI -0.46, -0.23; P = 9.77 × 10-09). This coefficient attenuated 10-fold upon adjustment for BMI at age 8 y, to -0.12 kg/m2 (or -0.03 SDs, 95% CI -0.13, 0.07; P = 0.55). Associations with blood pressure were similar, but associations across other traits were small and inconsistent. In negative control MR analyses, later age at menarche was associated with -0.77 kg/m2 of pre-pubertal BMI measured at age 8 y (or -0.39 SDs, 95% CI -0.50, -0.29; P = 6.28 × 10-13), indicating that variants influencing menarche also influence BMI before menarche. Cardiometabolic trait associations were weaker and less consistent among males and both sexes combined. Higher BMI at age 8 y (per 1 kg/m2 using 95 polymorphisms for BMI explaining 3.4% of variance) was associated with earlier menarche among 2,648 females (by -0.26 y, 95% CI -0.37, -0.16; P = 1.16 × 10-06), likewise among males and both sexes combined. In 2-sample MR analyses using 234 polymorphisms and inverse variance weighted (IVW) regression, each year later age at menarche was associated with -0.81 kg/m2 of adult BMI (or -0.17 SD units, 95% CI -0.21, -0.12; P = 4.00 × 10-15). Associations were weaker with cardiometabolic traits. Using 202 polymorphisms, later menarche was associated with lower odds of childhood obesity (IVW-based odds ratio = 0.52 per year later, 95% CI 0.48, 0.57; P = 6.64 × 10-15). Study limitations include modest sample sizes for 1-sample MR, lack of inference to non-white-European populations, potential selection bias through modest completion rates of puberty questionnaires, and likely disproportionate measurement error of exposures by sex. The cardiometabolic traits examined were heavily lipid-focused and did not include hormone-related traits such as insulin and insulin-like growth factors.ConclusionsOur results suggest that puberty timing has a small influence on adiposity and cardiometabolic traits and that preventive interventions should instead focus on reducing childhood adiposity.
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Project description:BackgroundPrevious studies of pubertal timing and self-harm are limited by subjective measures of pubertal timing or by the conflation of self-harm with suicide attempts and ideation. The current study investigates the association between an objective measure of pubertal timing - age at menarche - and self-harm with and without suicidal intent in adolescence and adulthood in females.MethodBirth cohort study based on 4042 females from the Avon Longitudinal Study of Parents and Children (ALSPAC). Age at menarche was assessed prospectively between ages 8 and 17 years. Lifetime history of self-harm was self-reported at ages 16 and 21 years. Associations between age at menarche and self-harm, both with and without suicidal intent, were examined using multivariable logistic regression.ResultsLater age at menarche was associated with a lower risk of lifetime self-harm at age 16 years (OR per-year increase in age at menarche 0.87; 95% CI 0.80-0.95). Compared with normative timing, early menarche (<11.5 years) was associated with an increased risk of self-harm (OR 1.31, 95% CI 1.04-1.64) and later menarche (>13.8 years) with a reduced risk (OR 0.74, 95% CI 0.58-0.93). The pattern of association was similar at age 21 years (OR per-year increase in age at menarche 0.92, 95% CI 0.85-1.00). There was no strong evidence for a difference in associations with suicidal v. non-suicidal self-harm.ConclusionsRisk of self-harm is higher in females with early menarche onset. Future research is needed to establish whether this association is causal and to identify potential mechanisms.
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Project description:BackgroundObesity has been shown to be associated with depression and it has been suggested that higher body mass index (BMI) increases the risk of depression and other common mental disorders. However, the causal relationship remains unclear and Mendelian randomisation, a form of instrumental variable analysis, has recently been employed to attempt to resolve this issue.AimsTo investigate whether higher BMI increases the risk of major depression.MethodTwo instrumental variable analyses were conducted to test the causal relationship between obesity and major depression in RADIANT, a large case-control study of major depression. We used a single nucleotide polymorphism (SNP) in FTO and a genetic risk score (GRS) based on 32 SNPs with well-established associations with BMI.ResultsLinear regression analysis, as expected, showed that individuals carrying more risk alleles of FTO or having higher score of GRS had a higher BMI. Probit regression suggested that higher BMI is associated with increased risk of major depression. However, our two instrumental variable analyses did not support a causal relationship between higher BMI and major depression (FTO genotype: coefficient -0.03, 95% CI -0.18 to 0.13, P = 0.73; GRS: coefficient -0.02, 95% CI -0.11 to 0.07, P = 0.62).ConclusionsOur instrumental variable analyses did not support a causal relationship between higher BMI and major depression. The positive associations of higher BMI with major depression in probit regression analyses might be explained by reverse causality and/or residual confounding.
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Project description:BACKGROUND:Despite many attempts to understand the genetic architecture of depression, little progress has been made. The majority of these studies, however, have been carried out in adults and do not account for the potential influence of development. METHODS:The Avon Longitudinal Study of Parents and Children (ALSPAC) is a longitudinal pregnancy cohort which recruited participants between April 1991 and December 1992. Analyses were replicated in two independent European cohorts. Genome-wide complex trait analysis (GCTA) software was used to investigate SNP-heritability (h2SNP) of depression across adolescence, the role of puberty was investigated by stratifying these estimates according to pubertal onset. Genome-wide association studies were performed to identify genetic variants associated with depression at different stages of development. RESULTS:Heritability was estimated between the ages of 11 and 18 with sample sizes ranging from 3289 to 5480. Heritability was low with an apparent peak was found at age 13 (h2 = 0.17, p = 0.006). Confidence intervals around these estimates suggest an upper-bound to h2SNP of around 30%. A variant located on chromosome 7 was found to be associated with depressive symptoms at age 13 in ALSPAC (rs138191010: ? = 0.142, p = 2.51 × 10-8), although this was not replicated. CONCLUSIONS:Although power is a potential limitation, the observed patterns provide interesting hypotheses surrounding the heritability of depression at different developmental stages. We found substantially lower estimates for depressive symptoms at age 11 (0.07) compared to those previously estimated in adults (0.21). We also found a peak in heritability at age 13. These findings suggest environmental factors are likely to be more important in the aetiology of depressive symptoms in early adolescence than in adulthood.
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