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- Mattsson, C. Mikael, et al.
(author)
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Sports genetics moving forward - lessons learned from medical research
- 2016
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In: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 48:3, s. 175-182
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Journal article (peer-reviewed)abstract
- Sports genetics can take advantage of lessons learned from human disease genetics. By righting past mistakes and increasing scientific rigor, the breadth and depth of knowledge in the field can be magnified. We present an outline of challenges facing sports genetics in the light of experiences from medical research.Sports performance is complex, resulting from a combination of a wide variety of different traits and attributes. Improving sports genetics will foremost require analyses based on detailed phenotyping. In order to find widely valid, reproducible common variants associated with athletic phenotypes, study sample sizes must be dramatically increased. One paradox is that in order to confirm relevance, replications in specific populations must be undertaken. Family studies of athletes may facilitate the discovery of rare variants with large effects on athletic phenotypes. The complexity of the human genome, combined with the complexity of athletic phenotypes, will require additional metadata and biological validation to identify a comprehensive set of genes involved.Analysis of personal genetic and multiomic profiles contribute to our conceptualization of precision medicine; the same will be the case in precision sports science. In the refinement of sports genetics it is essential to evaluate similarities and differences between genders and among ethnicities. Sports genetics to date have been hampered by small sample sizes and biased methodology which can lead to erroneous associations and overestimation of effect sizes. Consequently, currently available genetic tests based on these inherently limited data cannot predict athletic performance with any accuracy.
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- Mattsson, C. Mikael, et al.
(author)
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The ELITE project (Exercise at the Limit - Inherited Traits of Endurance) - the genetic profiles of the best endurance athletes in the world.
- 2017
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Conference paper (peer-reviewed)abstract
- Cardiovascular health exists as a spectrum of wellness and disease states. Moreover, a significant portion of what defines these states is due to genetics. We hypothesize that there exist genes and pathways that dually contribute to both disease and extreme health states. Interrogating the ‘adaptive’ tail of the distribution for individuals with extreme phenotypes, such as high maximum oxygen uptake (VO2max) in endurance athletes, will inform prevention, cause and treatment of pathogenic (‘maladaptive’) conditions. 1 To date, most genetic studies in the athlete population have examined a subset of genes (out of more than 21,000 in the genome), using small sample sizes and qualitative measures of performance. To the best of our knowledge, there has not been a comprehensive genetic study of endurance athletes with strict quantitative eligibility criteria.2-4The ELITE project (Exercise at the Limit – Inherited Traits of Endurance) intends to investigate the world’s best endurance athletes, i.e. individuals with extremely high VO2max. A primary goal is to determine what role genetic variation plays in athletic ability. One of the ancillary goals of the project is to understand the unique genetic differences contributing to extreme fitness in women versus men. We will sequence and analyze the genomes of elite level competitive athletes from various countries (including USA, Scandinavia, UK, Japan, and Brazil) who are highly successful in one of several endurance sports (such as running, cross country skiing, triathlon, cycling, rowing). We have recruited 750 elite athletes (142 women and 608 men) who have been consented and undergone enhanced whole exome sequencing and/or MEGA chip GWAS analysis. Inclusion criteria for the study restricts to the highest tail end (>99.98th percentile or 1/5000), i.e. VO2max >63 ml/kg for women and >75 ml/kg for men. Even with differential eligibility, skewed recruitment (1:4) is a challenge.Our preliminary results show tantalizing evidence for potentially beneficial genetic variants in several highly plausible genes. Additionally, pilot burden testing on a subset of the athletes also showed promising results. While already promising, rigorous analysis, increased sample size and orthogonal replication is required as our next step. Mattsson CM, Wheeler M, Waggott D, Caleshu C, Ashley EA. Sports genetics moving forward - lessons learned from medical research. Physiol Genomics. 2016; 48(3):175-182.Bouchard C, Sarzynski MA, Rice TK, Kraus WE, Church TS, Sung YJ, Rao DC, Rankinen T. Genomic predictors of the maximal O₂ uptake response to standardized exercise training programs. J Appl Physiol (1985). 2011; 110(5):1160-70.Eynon N, Morán M, Birk R, Lucia A. The champions' mitochondria: is it genetically determined? A review on mitochondrial DNA and elite athletic performance. Physiol Genomics. 2011;43(13):789-98.Pitsiladis YP, Tanaka M, Eynon N, Bouchard C, North KN, Williams AG, Collins M, Moran CN, Britton SL, Fuku N, Ashley EA, Klissouras V, Lucia A, Ahmetov II, de Geus E, Alsayrafi M; Athlome Project Consortium. Athlome Project Consortium: a concerted effort to discover genomic and other "omic" markers of athletic performance. Physiol Genomics. 2016;48(3):183-90.
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- Mather, Lisa, et al.
(author)
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An Underlying Common Factor, Influenced by Genetics and Unique Environment, Explains the Covariation Between Major Depressive Disorder, Generalized Anxiety Disorder, and Burnout : A Swedish Twin Study
- 2016
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In: Twin Research and Human Genetics. - : Cambridge University Press (CUP). - 1832-4274 .- 1839-2628. ; 19:6, s. 619-627
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Journal article (peer-reviewed)abstract
- Depression and anxiety are highly comorbid due to shared genetic risk factors, but less is known about whether burnout shares these risk factors. We aimed to examine whether the covariation between major depressive disorder (MDD), generalized anxiety disorder (GAD), and burnout is explained by common genetic and/or environmental factors. This cross-sectional study included 25,378 Swedish twins responding to a survey in 2005-2006. Structural equation models were used to analyze whether the trait variances and covariances were due to additive genetics, non-additive genetics, shared environment, and unique environment. Univariate analyses tested sex limitation models and multivariate analysis tested Cholesky, independent pathway, and common pathway models. The phenotypic correlations were 0.71 (0.69-0.74) between MDD and GAD, 0.58 (0.56-0.60) between MDD and burnout, and 0.53 (0.50-0.56) between GAD and burnout. Heritabilities were 45% for MDD, 49% for GAD, and 38% for burnout; no statistically significant sex differences were found. A common pathway model was chosen as the final model. The common factor was influenced by genetics (58%) and unique environment (42%), and explained 77% of the variation in MDD, 69% in GAD, and 44% in burnout. GAD and burnout had additive genetic factors unique to the phenotypes (11% each), while MDD did not. Unique environment explained 23% of the variability in MDD, 20% in GAD, and 45% in burnout. In conclusion, the covariation was explained by an underlying common factor, largely influenced by genetics. Burnout was to a large degree influenced by unique environmental factors not shared with MDD and GAD.
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- Mattsson, C. Mikael, et al.
(author)
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Informing women’s cardiovascular health through genomic analysis of extreme endurance athletes
- 2015
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Conference paper (peer-reviewed)abstract
- Cardiovascular health exists as a spectrum of wellness and disease states. We hypothesize that interrogating the tail ends of the distribution for individuals with extreme phenotypes, such as high VO2max in endurance athletes, will inform prevention, cause and treatment of pathogenic conditions. Mounting literature suggests that the physiological path to athletic performance is different among males and females. Traits with published sexual dichotomy include lactate threshold, efficiency, heat management, and fat metabolism. To define the genetic roots of this dichotomy, we propose to investigate sex-specific genetic determinants of VO2max among elite endurance athletes. We have recruited 36 female (VO2max>63 ml/kg; >99.99th percentile) and 129 male (>75 ml/kg) elite athletes (n=167) who have been consented and undergone enhanced whole exome sequencing. Even with differential eligibility, skewed recruitment (1:3.5) is a challenge. We will recruit a total of 100 female and 156 male elite athletes, and analyze these 256 exomes for burden of rare genetic variation that may impact sex-specific determinants of VO2max. We will combine these data with an additional 1850 samples of elite athletes to evaluate for common variants that have sex-specific effects on VO2max. Lastly, we will do a sex specific genetic cohort comparison of endurance athletes with existing collections of cardiovascular disease patients. Our preliminary results show tantalizing evidence for several highly plausible sex specific genes, including androgen receptor (AR) and FTO. The AR is the target of several known performance enhancing drugs, such as testosterone. FTO is associated with numerous aspects of body composition, energy management and even some evidence for age of menarche. While already promising, rigorous analysis, increased sample size and orthogonal replication is required as our next step.
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| 6. |
- Waggott, Daryl, et al.
(author)
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The Genomics of Extreme Athletes. The ELITE Study (Exercise at the Limit - Inherited Traits of Endurance).
- 2016
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Conference paper (peer-reviewed)abstract
- Health exists as a spectrum from disease to some outlier physiological optimum. To date most molecular genetic research has focused on disease states and less on extreme health populations. We hypothesize that interrogating outlier elite endurance athletes, with strict physiological eligibility criteria, will inform cardiovascular research through the identification of complementary pathways and therapeutic targets. Eligibility criteria for the ELITE study required a lifetime VO2max, which measures maximal oxygen consumption during peak aerobic exercise, at a threshold estimated to be attainable in less than 1 in 50,000 people (men 80ml/kg/min; women 65ml/kg/min). VO2max is reported to have substantial genetic influence (h2~0.5) and is correlated with endurance sport performance along with work efficiency. Several well documented cases of athletic outliers have been tied to rare genetic variants including the Finnish cross country skier Mäntyranta (EPOR) and Priscilla Lopes-Schliep (LMNA). In the later, the same domain of the LMNA gene is related to rare forms of muscular dystrophy. Additionally, adaptive hypoxia variations have been identified in high altitude populations in Tibet (EPAS1), Andes and Ethiopia. To date we have sequenced 268 ELITE participants using clinically enhanced exomes and run 550 samples on high density multi-ethnic SNP chips. Preliminary analysis has focused on a combination of rare variant curation and common variation association. Rare variation curation included prioritization of LOF variants within candidate genes related to oxygen transport, muscle physiology and metabolism (i.e. PPARA, PPARGC1A, RYR2, ACTN3) and global gene screening using in silico weighted burden testing. Common variant association (the largest GWAS of its kind) has been used to support rare variant findings and identify non-coding and structural variant association signals. We believe that our methodology of combining rare LOF variants with common variation association in a population with extreme endurance physiology will systematically identify pleiotropic genes with both protective and pathogenic features similar to PCSK9.
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