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Abstract Mitochondrial DNA copy number (mtDNA-CN) is a biomarker for mitochondrial dysfunction associated with several diseases. Previous genome-wide association studies (GWAS) have been performed to unravel underlying mechanisms of mtDNA-CN regulation. However, the identified gene regions explain only a small fraction of mtDNA-CN variability. Most of this data has been estimated from microarrays based on various pipelines. In the present study we aimed to (1) identify genetic loci for qPCR-measured mtDNA-CN from three studies (16,130 participants) using GWAS, (2) identify potential systematic differences between our qPCR derived mtDNA-CN measurements compared to the published microarray intensity-based estimates, and (3) disentangle the nuclear from mitochondrial regulation of the mtDNA-CN phenotype. We identified two genome-wide significant autosomal loci associated with qPCR-measured mtDNA-CN: at HBS1L (rs4895440, p = 3.39 × 10–13) and GSDMA (rs56030650, p = 4.85 × 10–08) genes. Moreover, 113/115 of the previously published SNPs identified by microarray-based analyses were significantly equivalent with our findings. In our study, the mitochondrial genome itself contributed only marginally to mtDNA-CN regulation as we only detected a single rare mitochondrial variant associated with mtDNA-CN. Furthermore, we incorporated mitochondrial haplogroups into our analyses to explore their potential impact on mtDNA-CN. However, our findings indicate that they do not exert any significant influence on our results.

Abstract X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.

Identifying causal variants and genes in genome-wide association studies remains a challenge, an issue that is ameliorated with larger sample sizes. Here the authors meta-analyze kidney function genome-wide association studies to identify new loci and fine-map loci to home in on variants and genes involved in kidney function.

Age-related macular degeneration (AMD) is a vision impairing disease of the central retina characterized by early and late forms in individuals older than 50 years of age. However, there is little knowledge to what extent also younger adults are affected. We have thus set out to estimate the prevalence of early AMD features and late AMD in a general adult population by acquiring color fundus images in 2,840 individuals aged 25 to 74 years of the Cooperative Health Research in the Region of Augsburg project (KORA) in South Germany. Among the 2,546 participants with gradable images for each eye, 10.9% (n = 277) had early AMD features (applying the 9-step Age-Related Eye Disease Study Severity Scale), 0.2% (n = 6) had late AMD. Prevalence increased with age, reaching 26.3% for early AMD features and 1.9% for late AMD at the age 70+. However, signs of early AMD were found in subjects as young as 25 years, with the risk for early AMD features increasing linearly by years of age in men, and, less consistent with a linear increase, in women. Risk for early AMD features increased linearly by pack years of smoking in men, not in women, nor was there any association with other lifestyle or metabolic factors. By providing much sought-after prevalence estimates for AMD from Central Europe, our data underscores a substantial proportion of the adult population with signs of early AMD, including individuals younger than 50 years. This supports the notion that early AMD features in the young might be under-acknowledged.