Transient modification of lin28b expression - Permanent effects on zebrafish growth

Recent genome-wide association studies and mouse models have identified LIN28B as a gene affecting several pubertal timing-related traits and vertebrate growth. However, the exact biological mechanisms underlying the associations remain unknown. We have explored the mechanisms linking LIN28B with growth regulation by combining human gene expression data with functional models. Specifically, we show that 1) pubertal timing-associated genetic variation correlates with LIN28B expression in the pituitary and hypothalamus, 2) downregulating lin28b in zebrafish embryos associates with aberrant development of kiss2-neurons, and 3) increasing lin28b expression transiently by synthetic mRNA injections during embryogenesis results in sustained enhancement of zebrafish growth. Unexpectedly, the mRNA injections resulted in advanced sexual maturation of female fish, suggesting that lin28b may influence pubertal timing through multiple developmental mechanisms. Overall, these results provide novel insight into LIN28B function in vertebrate growth regulation, emphasizing the importance of the gene and related genetic pathways for embryonic and juvenile development.Peer reviewe

Integration of questionnaire-based risk factors improves polygenic risk scores for human coronary heart disease and type 2 diabetes

Max Tamlander et al. combine polygenic risk scores and clinical assessments to improve prediction of coronary artery disease and type 2 diabetes in European cohorts. Taken together, their results provide a useful method for preliminary cardiometabolic risk assessment in patients. Large-scale biobank initiatives and commercial repositories store genomic data collected from millions of individuals, and tools to leverage the rapidly growing pool of health and genomic data in disease prevention are needed. Here, we describe the derivation and validation of genomics-enhanced risk tools for two common cardiometabolic diseases, coronary heart disease and type 2 diabetes. Data used for our analyses include the FinnGen study (N = 309,154) and the UK Biobank project (N = 343,672). The risk tools integrate contemporary genome-wide polygenic risk scores with simple questionnaire-based risk factors, including demographic, lifestyle, medication, and comorbidity data, enabling risk calculation across resources where genome data is available. Compared to routinely used clinical risk scores for coronary heart disease and type 2 diabetes prevention, the risk tools show at least equivalent risk discrimination, improved risk reclassification (overall net reclassification improvements ranging from 3.7 [95% CI 2.8-4.6] up to 6.2 [4.6-7.8]), and capacity to be improved even further with standard lipid and blood pressure measurements. Without the need for blood tests or evaluation by a health professional, the risk tools provide a powerful yet simple method for preliminary cardiometabolic risk assessment for individuals with genome data available.Peer reviewe

Lipidome- and Genome-Wide Study to Understand Sex Differences in Circulatory Lipids

Background Despite well-recognized differences in the atherosclerotic cardiovascular disease risk between men and women, sex differences in risk factors and sex-specific mechanisms in the pathophysiology of atherosclerotic cardiovascular disease remain poorly understood. Lipid metabolism plays a central role in the development of atherosclerotic cardiovascular disease. Understanding sex differences in lipids and their genetic determinants could provide mechanistic insights into sex differences in atherosclerotic cardiovascular disease and aid in precise risk assessment. Herein, we examined sex differences in plasma lipidome and heterogeneity in genetic influences on lipidome in men and women through sex-stratified genome-wide association analyses. Methods and Results We used data consisting of 179 lipid species measured by shotgun lipidomics in 7266 individuals from the Finnish GeneRISK cohort and sought for replication using independent data from 2045 participants. Significant sex differences in the levels of 141 lipid species were observed (PPeer reviewe

Associations Between Attention-Deficit/Hyperactivity Disorder and Various Eating Disorders : A Swedish Nationwide Population Study Using Multiple Genetically Informative Approaches

BACKGROUND: Although attention-deficit/hyperactivity disorder (ADHD) and eating disorders (EDs) frequently cooccur, little is known about the shared etiology. In this study, we comprehensively investigated the genetic association between ADHD and various EDs, including anorexia nervosa (AN) and other EDs such as bulimia nervosa. METHODS: We applied different genetically informative designs to register-based information of a Swedish nationwide population (N = 3,550,118). We first examined the familial coaggregation of clinically diagnosed ADHD and EDs across multiple types of relatives. We then applied quantitative genetic modeling in full-sisters and maternal half-sisters to estimate the genetic correlations between ADHD and EDs. We further tested the associations between ADHD polygenic risk scores and ED symptoms, and between AN polygenic risk scores and ADHD symptoms, in a genotyped population-based sample (N = 13,472). RESULTS: Increased risk of all types of EDs was found in individuals with ADHD (any ED: odds ratio [OR] = 3.97, 95% confidence interval [CI] = 3.81, 4.14; AN: OR = 2.68, 95% CI = 2.15, 2.86; other EDs: OR = 4.66, 95% CI = 4.47, 4.87; bulimia nervosa: OR = 5.01, 95% CI = 4.63, 5.41) and their relatives compared with individuals without ADHD and their relatives. The magnitude of the associations decreased as the degree of relatedness decreased, suggesting shared familial liability between ADHD and EDs. Quantitative genetic models revealed stronger genetic correlation of ADHD with other EDs (.37, 95% CI = .31, .42) than with AN (.14, 95% CI = .05, .22). ADHD polygenic risk scores correlated positively with ED symptom measures overall and with the subscales Drive for Thinness and Body Dissatisfaction despite small effect sizes. CONCLUSIONS: We observed stronger genetic association with ADHD for non-AN EDs than for AN, highlighting specific genetic correlation beyond a general genetic factor across psychiatric disorders.Peer reviewe

A trans-ancestral meta-analysis of genome-wide association studies reveals loci associated with childhood obesity

Although hundreds of genome-wide association studies-implicated loci have been reported for adult obesity-related traits, less is known about the genetics specific for early-onset obesity and with only a few studies conducted in non-European populations to date. Searching for additional genetic variants associated with childhood obesity, we performed a trans-ancestral meta-analysis of 30 studies consisting of up to 13005 cases (>= 95th percentile of body mass index (BMI) achieved 2-18 years old) and 15599 controls (consistentlyPeer reviewe

Association of LIN28B with Adult Adiposity-Related Traits in Females

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Genome Wide Association Identifies Common Variants at the SERPINA6/SERPINA1 Locus Influencing Plasma Cortisol and Corticosteroid Binding Globulin

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Effectiveness and feasibility of cardiovascular disease personalised prevention on high polygenic risk score subjects: a randomised controlled pilot study

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The role of polygenic risk and susceptibility genes in breast cancer over the course of life

Polygenic risk scores (PRS) for breast cancer have potential to improve risk prediction, but there is limited information on their utility in various clinical situations. Here we show that among 122,978 women in the FinnGen study with 8401 breast cancer cases, the PRS modifies the breast cancer risk of two high-impact frameshift risk variants. Similarly, we show that after the breast cancer diagnosis, individuals with elevated PRS have an elevated risk of developing contralateral breast cancer, and that the PRS can considerably improve risk assessment among their female first-degree relatives. In more detail, women with the c.1592delT variant in PALB2 (242-fold enrichment in Finland, 336 carriers) and an average PRS (10-90(th) percentile) have a lifetime risk of breast cancer at 55% (95% CI 49-61%), which increases to 84% (71-97%) with a high PRS (>90(th) percentile), and decreases to 49% (30-68%) with a low PRS (Peer reviewe

LIN28B affects gene expression at the hypothalamic-pituitary axis and serum testosterone levels

Genome-wide association studies (GWAS) have recurrently associated sequence variation nearby LIN28B with pubertal timing, growth and disease. However, the biology linking LIN28B with these traits is still poorly understood. With our study, we sought to elucidate the mechanisms behind the LIN28B associations, with a special focus on studying LIN28B function at the hypothalamic-pituitary (HP) axis that is ultimately responsible for pubertal onset. Using CRISPR-Cas9 technology, we first generated lin28b knockout (KO) zebrafish. Compared to controls, the lin28b KO fish showed both accelerated growth tempo, reduced adult size and increased expression of mitochondrial genes during larval development. Importantly, data from the knockout zebrafish models and adult humans imply that LIN28B expression has potential to affect gene expression in the HP axis. Specifically, our results suggest that LIN28B expression correlates positively with the expression of ESR1 in the hypothalamus and POMC in the pituitary. Moreover, we show how the pubertal timing advancing allele (T) for rs7759938 at the LIN28B locus associates with higher testosterone levels in the UK Biobank data. Overall, we provide novel evidence that LIN28B contributes to the regulation of sex hormone pathways, which might help explain why the gene associates with several distinct traits.Peer reviewe