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Age at menopause (AOM) has a substantial impact on fertility and disease risk. While many loci with variants that associate with AOM have been identified through genome-wide association studies (GWAS) under an additive model, other genetic models are rarely considered 1 . Here through GWAS meta-analysis under the recessive model of 174,329 postmenopausal women from Iceland, Denmark, the United Kingdom (UK; UK Biobank) and Norway, we study low-frequency variants with a large effect on AOM. We discovered that women homozygous for the stop-gain variant rs117316434 (A) in CCDC201 (p.(Arg162Ter), minor allele frequency ~1%) reached menopause 9 years earlier than other women (P = 1.3 × 10 -15 ). The genotype is present in one in 10,000 northern European women and leads to primary ovarian insufficiency in close to half of them. Consequently, homozygotes have fewer children, and the age at last childbirth is 5 years earlier (P = 3.8 × 10 -5 ). The CCDC201 gene was only found in humans in 2022 and is highly expressed in oocytes. Homozygosity for CCDC201 loss-of-function has a substantial impact on female reproductive health, and homozygotes would benefit from reproductive counseling and treatment for symptoms of early menopause., (© 2024. The Author(s).)

Iron is essential for many biological functions and iron deficiency and overload have major health implications. We performed a meta-analysis of three genome-wide association studies from Iceland, the UK and Denmark of blood levels of ferritin (N = 246,139), total iron binding capacity (N = 135,430), iron (N = 163,511) and transferrin saturation (N = 131,471). We found 62 independent sequence variants associating with iron homeostasis parameters at 56 loci, including 46 novel loci. Variants at DUOX2, F5, SLC11A2 and TMPRSS6 associate with iron deficiency anemia, while variants at TF, HFE, TFR2 and TMPRSS6 associate with iron overload. A HBS1L-MYB intergenic region variant associates both with increased risk of iron overload and reduced risk of iron deficiency anemia. The DUOX2 missense variant is present in 14% of the population, associates with all iron homeostasis biomarkers, and increases the risk of iron deficiency anemia by 29%. The associations implicate proteins contributing to the main physiological processes involved in iron homeostasis: iron sensing and storage, inflammation, absorption of iron from the gut, iron recycling, erythropoiesis and bleeding/menstruation.

Background Polygenic risk scores (PRSs) based on risk variants from genome-wide association studies predict coronary artery disease (CAD) risk. However, it is unknown whether the PRS is associated with specific CAD characteristics. Methods and Results We consecutively included 1645 patients with suspected stable CAD undergoing coronary computed tomography angiography. A multilocus PRS was calculated as the weighted sum of CAD risk variants. Plaques were evaluated using an 18-segment model and characterized by stenosis severity and composition (soft [0%-19% calcified], mixed-soft [20%-49% calcified], mixed-calcified [50%-79% calcified], or calcified [≥80% calcified]). Coronary artery calcium score and segment stenosis score were used to characterize plaque burden. For each standard deviation increase in the PRS, coronary artery calcium score increased by 78% ( P =4.1e-26) and segment stenosis score increased by 16% ( P =2.4e-29) in the fully adjusted model. The PRS was associated with a higher prevalence of obstructive plaques (odds ratio [OR ] : 1.78, P =5.6e-16), calcified (OR: 1.69, P =6.5e-17), mixed-calcified (OR: 1.67, P =7.3e-9), mixed-soft (OR: 1.45, P =1.6e-6), and soft plaques (OR: 1.49, P =2.5e-6), and a higher prevalence of plaque in each coronary vessel (all P <1.0e-4). However, when analyzing data on a plaque level (3007 segments with plaque in 849 patients) the PRS was not associated with stenosis severity, plaque composition, or localization (all P >0.05). Conclusions Our results suggest that polygenic risk based on large genome-wide association studies increases CAD risk through an increased burden of coronary atherosclerosis rather than promoting specific plaque features. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT02264717.

Earlier menarche correlates with shorter adult height and higher childhood body fat. We conducted a genome-wide association study of age at menarche (AAM) on 15,297 Icelandic women. Combined analysis with replication sets from Iceland, Denmark and the Netherlands (N = 10,040) yielded a significant association between rs314280[T] on 6q21, near the LIN28B gene, and AAM (effect = 1.2 months later per allele; P = 1.8 × 10(-14)). A second SNP within the same linkage disequilibrium (LD) block, rs314277, splits rs314280[T] into two haplotypes with different effects (0.9 months and 1.9 months per allele). These variants have been associated with greater adult height. The association with adult height did not account for the association with AAM or vice versa. Other variants, previously associated with height, did not associate significantly with AAM. Given the link between body fat and AAM, we also assessed 11 variants recently associated with higher body mass index (BMI) and 5 of those associated with earlier AAM.