Population health research is increasingly focused on the genetic determinants of healthy ageing, but there is no public resource of whole genome sequences and phenotype data from healthy elderly individuals. Here we describe the first release of the Medical Genome Reference Bank (MGRB), comprising whole genome sequence and phenotype of 2570 elderly Australians depleted for cancer, cardiovascular disease, and dementia. We analyse the MGRB for single-nucleotide, indel and structural variation in the nuclear and mitochondrial genomes. MGRB individuals have fewer disease-associated common and rare germline variants, relative to both cancer cases and the gnomAD and UK Biobank cohorts, consistent with risk depletion. Age-related somatic changes are correlated with grip strength in men, suggesting blood-derived whole genomes may also provide a biologic measure of age-related functional deterioration. The MGRB provides a broadly applicable reference cohort for clinical genetics and genomic association studies, and for understanding the genetics of healthy ageing.

BACKGROUND: Exercise-induced cardiac remodeling can be profound, resulting in clinical overlap with dilated cardiomyopathy, yet the significance of reduced ejection fraction (EF) in athletes is unclear. The aim is to assess the prevalence, clinical consequences, and genetic predisposition of reduced EF in athletes. METHODS: Young endurance athletes were recruited from elite training programs and underwent comprehensive cardiac phenotyping and genetic testing. Those with reduced EF using cardiac magnetic resonance imaging (defined as left ventricular EF <50%, or right ventricular EF 100 ventricular premature beats/24 h; P =0.008) and lower left ventricular global longitudinal strain (–17%±2% versus –19%±2%; P 95%. CONCLUSIONS: Reduced EF occurs in approximately 1 in 6 elite endurance athletes and is related to genetic predisposition in addition to exercise training. Genetic and imaging markers may help identify endurance athletes in whom scrutiny about long-term clinical outcomes may be appropriate. REGISTRATION: URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374976&isReview=true ; Unique identifier: ACTRN12618000716268.

Cancer genetics has to date focused on epithelial malignancies, identifying multiple histotype-specific pathways underlying cancer susceptibility. Sarcomas are rare malignancies predominantly derived from embryonic mesoderm. To identify pathways specific to mesenchymal cancers, we performed whole-genome germline sequencing on 1644 sporadic cases and 3205 matched healthy elderly controls. Using an extreme phenotype design, a combined rare-variant burden and ontologic analysis identified two sarcoma-specific pathways involved in mitotic and telomere functions. Variants in centrosome genes are linked to malignant peripheral nerve sheath and gastrointestinal stromal tumors, whereas heritable defects in the shelterin complex link susceptibility to sarcoma, melanoma, and thyroid cancers. These studies indicate a specific role for heritable defects in mitotic and telomere biology in risk of sarcomas.

Background: Spontaneous coronary artery dissection (SCAD) is a cause of acute coronary syndrome that predominantly affects women. Its pathophysiology remains unclear but connective tissue disorders (CTD) and other vasculopathies have been observed in many SCAD patients. A genetic component for SCAD is increasingly appreciated, although few genes have been robustly implicated. We sought to clarify the genetic cause of SCAD using targeted and genome-wide methods in a cohort of sporadic cases to identify both common and rare disease-associated variants. Methods: A cohort of 91 unrelated sporadic SCAD cases was investigated for rare, deleterious variants in genes associated with either SCAD or CTD, while new candidate genes were sought using rare variant collapsing analysis and identification of novel loss-of-function variants in genes intolerant to such variation. Finally, 2 SCAD polygenic risk scores were applied to assess the contribution of common variants. Results: We identified 10 cases with at least one rare, likely disease-causing variant in CTD-associated genes, although only one had a CTD phenotype. No genes were significantly associated with SCAD from genome-wide collapsing analysis, however, enrichment for TGF (transforming growth factor)-β signaling pathway genes was found with analysis of 24 genes harboring novel loss-of-function variants. Both polygenic risk scores demonstrated that sporadic SCAD cases have a significantly elevated genetic SCAD risk compared with controls. Conclusions: SCAD shares some genetic overlap with CTD, even in the absence of any major CTD phenotype. Consistent with a complex genetic architecture, SCAD patients also have a higher burden of common variants than controls.

Mitochondrial dysfunction, due to mutations of the gene encoding succinate dehydrogenase (SDH), has been implicated in the development of adrenal phaeochromocytomas, sympathetic and parasympathetic paragangliomas, renal cell carcinomas, gastrointestinal stromal tumours and more recently pituitary tumours. Underlying mechanisms behind germline SDH subunit B (SDHB) mutations and their associated risk of disease are not clear. To investigate genotype–phenotype correlation of SDH subunit B (SDHB) variants, a homology model for humanSDHwas developed from a crystallographic structure.SDHBmutations were mapped, and biochemical effects of these mutations were predictedin silico. Results of structural modelling indicated that many mutations withinSDHBare predicted to cause either failure of functionalSDHBexpression (p.Arg27*, p.Arg90*, c.88delC and c.311delAinsGG), or disruption of the electron path (p.Cys101Tyr, p.Pro197Arg and p.Arg242His). GFP-tagged WTSDHBand mutantSDHBconstructs were transfected (HEK293) to determine biological outcomes of these mutantsin vitro. According toin silicopredictions, specificSDHBmutations resulted in impaired mitochondrial localisation and/or SDH enzymatic activity. These results indicated strong genotype–functional correlation forSDHBvariants. This study reveals new insights into the effects ofSDHBmutations and the power of structural modelling in predicting biological consequences. We predict that our functional assessment ofSDHBmutations will serve to better define specific consequences for SDH activity as well as to provide a much needed assay to distinguish pathogenic mutations from benign variants.

Background and Aims: Endurance sport has been associated with an increased risk of atrial fibrillation (AF). The aim of this study was to assess the extent to which this is due to exercise burden or genetic predisposition. Methods: Former rowers aged 45–80 years who competed at international championships were compared with a control group extracted from the UK Biobank, matched (1:100) for age and sex. Evaluation included 12-lead and Holter electrocardiograms, cardiac magnetic resonance imaging, and genetic analyses including rare variant evaluation and derivation of a validated AF polygenic risk score (AF-PRS). Results: Of 121 rowers [age 62 years (interquartile range 54–69), 74% male], 26 (21.5%) had AF as compared with 364 of 11 495 control subjects (3.2%), prevalence risk ratio 6.8 [95% confidence interval (CI) 4.7–9.8]. Incident AF over 4-year follow-up was also greater [6 of 95 rowers (6.3%) vs 252 of 11 131 controls (2.3%), hazard ratio 2.8 (95% CI 1.6–5.0)]. Compared with controls, athletes demonstrated greater structural and electrophysiological cardiac remodelling. Athletes had similar cardiovascular risk factor profiles but a higher stroke prevalence than controls [3.3% vs 1.1%, risk ratio 3.0 (95% CI 1.1–7.9)]. Rare pathogenic and likely pathogenic variants in cardiomyopathy genes had low prevalence in athletes (2.7%) and were not enriched in those with AF. In contrast, in those subjects with a high AF-PRS (defined by the upper quartile in a healthy reference population) the odds of having AF increased 3.7-fold in athletes (95% CI 1.5–9.4) and 2.0-fold in controls (95% CI 1.7–2.4; P = .37 for between-group comparisons). Conclusions: Despite having a favourable cardiovascular risk factor profile compared with controls, elite endurance athletes had a markedly higher prevalence and incidence of AF. These data suggest that exercise-induced cardiac remodelling and genetic susceptibility contribute to AF in endurance athletes.