Association of milk intake with hay fever, asthma, and lung function: a Mendelian randomization analysis.

BACKGROUND: Previous observational studies have indicated a protective effect of drinking milk on asthma and allergy. In Mendelian Randomization, one or more genetic variants are used as unbiased markers of exposure to examine causal effects. We examined the causal effect of milk intake on hay fever, asthma, forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) by using the lactase rs4988235 genotype associated with milk intake. METHODS: We performed a Mendelian Randomization study including 363,961 participants from the UK Biobank. RESULTS: Observational analyses showed that self-reported milk-drinkers vs. non-milk drinkers had an increased risk of hay fever: odds ratio (OR) = 1.36 (95% CI 1.32, 1.40, p < 0.001), asthma: OR = 1.33 (95% CI 1.38, 1.29, p < 0.001), yet a higher FEV1: ß = 0.022 (SE = 0.004, p < 0.001) and FVC: ß = 0.026 (SE = 0.005, p < 0.001). In contrast, genetically determined milk-drinking vs. not drinking milk was associated with a lower risk of hay fever: OR = 0.791 (95% CI 0.636, 0.982, p = 0.033), and asthma: OR = 0.587 (95% CI 0.442, 0.779, p = 0.001), and lower FEV1: ß = - 0.154 (standard error, SE = 0.034, p < 0.001) liter, and FVC: ß = - 0.223 (SE = 0.034, p < 0.001) liter in univariable MR analyses. These results were supported by multivariable Mendelian randomization analyses although not statistically significant. CONCLUSIONS: As opposed to observational results, genetic association findings indicate that drinking milk has a protective effect on hay fever and asthma but may also have a negative effect on lung function. The results should be confirmed in other studies before any recommendations can be made.

Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity.

Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The missense variant Val94Met (rs17151919) in LEP was common in individuals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry (P = 2 × 10-16, n = 3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting that leptin regulates early adiposity.

Genetic variation, adipokines, and cardiometabolic disease.

Adipokines are adipocyte-secreted cell signalling proteins that travel to distant target organs and tissues, where they regulate a variety of biological actions implicated in cardiometabolic health. In the past decade, genome-wide association studies have identified multiple genetic variants associated with circulating levels of adipokines, providing new instruments for examining the role of adipokines in cardiometabolic pathologies. Currently, there is limited genetic evidence of causal relationships between adipokines and cardiometabolic disease, which is consistent with findings from randomized clinical trials that have thus far shown limited success for adipokine-based treatments in improving cardiometabolic health. Incorporating human genetic data in early phases of target selection is essential for enhancing the success of adipokine-based therapies for cardiometabolic disease.

Analysis of case-parent trios for imprinting effect using a loglinear model with adjustment for sex-of-parent-specific transmission ratio distortion.

Transmission ratio distortion (TRD) is a phenomenon where parental transmission of disease allele to the child does not follow the Mendelian inheritance ratio. TRD occurs in a sex-of-parent-specific or non-sex-of-parent-specific manner. An offset computed from the transmission probability of the minor allele in control-trios can be added to the loglinear model to adjust for TRD. Adjusting the model removes the inflation in the genotype relative risk (RR) estimate and Type 1 error introduced by non-sex-of-parent-specific TRD. We now propose to further extend this model to estimate an imprinting parameter. Some evidence suggests that more than 1% of all mammalian genes are imprinted. In the presence of imprinting, for example, the offspring inheriting an over-transmitted disease allele from the parent with a higher expression level in a neighboring gene is over-represented in the sample. TRD mechanisms such as meiotic drive and gametic competition occur in a sex-of-parent-specific manner. Therefore, sex-of-parent-specific TRD (ST) leads to over-representation of maternal or paternal alleles in the affected child. As a result, ST may bias the imprinting effect when present in the sample. We propose a sex-of-parent-specific transmission offset in adjusting the loglinear model to account for ST. This extended model restores the correct RR estimates for child and imprinting effects, adjusts for inflation in Type 1 error, and improves performance on sensitivity and specificity compared to the original model without ST offset. We conclude that to correctly interpret the association signal of an imprinting effect, adjustment for ST is necessary to ensure valid conclusions.

Transmission ratio distortion: review of concept and implications for genetic association studies.

Transmission ratio distortion (TRD) occurs when one of the two alleles from either parent is preferentially transmitted to the offspring. This leads to a statistical departure from the Mendelian law of inheritance, which states that each of the two parental alleles is transmitted to offspring with a probability of 0.5. A number of mechanisms are thought to induce TRD such as meiotic drive, gametic competition, and embryo lethality. TRD has been extensively studied in animals, but the prevalence of TRD in humans remains largely unknown. Nevertheless, understanding the TRD phenomenon and taking it into consideration in many aspects of human genetics has potential benefits that have not been sufficiently emphasized in the current literature. In this review, we discuss the importance of TRD in three distinct but related fields of genetics: developmental genetics which studies the genetic abnormalities in zygotic and embryonic development, statistical genetics/genetic epidemiology which utilizes population study designs and statistical models to interpret the role of genes in human health, and population genetics which is concerned with genetic diversity in populations in an evolutionary context. From the perspective of developmental genetics, studying TRD leads to the identification of the processes and mechanisms for differential survival observed in embryos. As a result, it is a genetic force which affects allele frequency at the population, as well as, at the organismal level. Therefore, it has implications on genetic diversity of the population over time. From the perspective of genetic epidemiology, the TRD influence on a marker locus is a confounding factor which has to be adequately dealt with to correctly interpret linkage or association study results. These aspects are developed in this review. In addition to these theoretical notions, a brief summary of the empirical evidence of the TRD phenomenon in human and mouse studies is provided. The objective of our paper is to show the potentially important role of TRD in many areas of genetics, and to create an incentive for future research.