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Little is known about the biology of back pain, a leading cause of disability. Here the authors report 30 new back pain loci, implicating genes involved in cartilage/bone biology, as well as neurological and inflammatory processes.

This article discusses the effect of gonadotrophin releasing hormone analogue on sebum excretion rates and hair size in hirsute women. Hirsuties has been attributed to excessive androgen metabolism within skin although most women with hirsuties have normal or only slightly elevated plasma levels of testosterone. Gonadotrophin releasing hormone analogues abolish ovarian sex steroid production and this study examines their effect, with oestrogen replacement, on sebaceous gland activity and hair growth in a group of normal cycling mildly hirsute women. Sixteen patients with idiopathic hirsuties, with normal menstrual cycles, adrenal function, luteinising hormone and a body mass index between 19 and 25 were studied.

Human genetic studies of common variants have provided substantial insight into the biological mechanisms that govern ovarian ageing 1 . Here we report analyses of rare protein-coding variants in 106,973 women from the UK Biobank study, implicating genes with effects around five times larger than previously found for common variants (ETAA1, ZNF518A, PNPLA8, PALB2 and SAMHD1). The SAMHD1 association reinforces the link between ovarian ageing and cancer susceptibility 1 , with damaging germline variants being associated with extended reproductive lifespan and increased all-cause cancer risk in both men and women. Protein-truncating variants in ZNF518A are associated with shorter reproductive lifespan-that is, earlier age at menopause (by 5.61 years) and later age at menarche (by 0.56 years). Finally, using 8,089 sequenced trios from the 100,000 Genomes Project (100kGP), we observe that common genetic variants associated with earlier ovarian ageing associate with an increased rate of maternally derived de novo mutations. Although we were unable to replicate the finding in independent samples from the deCODE study, it is consistent with the expected role of DNA damage response genes in maintaining the genetic integrity of germ cells. This study provides evidence of genetic links between age of menopause and cancer risk., (© 2024. The Author(s).)

Autoimmune thyroid disease (AITD) is a common autoimmune disease. In a GWAS meta-analysis of 110,945 cases and 1,084,290 controls, 290 sequence variants at 225 loci are associated with AITD. Of these variants, 115 are previously unreported. Multiomics analysis yields 235 candidate genes outside the MHC-region and the findings highlight the importance of genes involved in T-cell regulation. A rare 5'-UTR variant (rs781745126-T, MAF = 0.13% in Iceland) in LAG3 has the largest effect (OR = 3.42, P = 2.2 × 10 -16 ) and generates a novel start codon for an open reading frame upstream of the canonical protein translation initiation site. rs781745126-T reduces mRNA and surface expression of the inhibitory immune checkpoint LAG-3 co-receptor on activated lymphocyte subsets and halves LAG-3 levels in plasma among heterozygotes. All three homozygous carriers of rs781745126-T have AITD, of whom one also has two other T-cell mediated diseases, that is vitiligo and type 1 diabetes. rs781745126-T associates nominally with vitiligo (OR = 5.1, P = 6.5 × 10 -3 ) but not with type 1 diabetes. Thus, the effect of rs781745126-T is akin to drugs that inhibit LAG-3, which unleash immune responses and can have thyroid dysfunction and vitiligo as adverse events. This illustrates how a multiomics approach can reveal potential drug targets and safety concerns., (© 2024. The Author(s).)

Clonal hematopoiesis (CH) arises when a substantial proportion of mature blood cells is derived from a single hematopoietic stem cell lineage. Using whole-genome sequencing of 45,510 Icelandic and 130,709 UK Biobank participants combined with a mutational barcode method, we identified 16,306 people with CH. Prevalence approaches 50% in elderly participants. Smoking demonstrates a dosage-dependent impact on risk of CH. CH associates with several smoking-related diseases. Contrary to published claims, we find no evidence that CH is associated with cardiovascular disease. We provide evidence that CH is driven by genes that are commonly mutated in myeloid neoplasia and implicate several new driver genes. The presence and nature of a driver mutation alters the risk profile for hematological disorders. Nevertheless, most CH cases have no known driver mutations. A CH genome-wide association study identified 25 loci, including 19 not implicated previously in CH. Splicing, protein and expression quantitative trait loci were identified for CD164 and TCL1A., (© 2023. The Author(s).)

Background: In 2021, the American College of Medical Genetics and Genomics (ACMG) recommended reporting actionable genotypes in 73 genes associated with diseases for which preventive or therapeutic measures are available. Evaluations of the association of actionable genotypes in these genes with life span are currently lacking., Methods: We assessed the prevalence of coding and splice variants in genes on the ACMG Secondary Findings, version 3.0 (ACMG SF v3.0), list in the genomes of 57,933 Icelanders. We assigned pathogenicity to all reviewed variants using reported evidence in the ClinVar database, the frequency of variants, and their associations with disease to create a manually curated set of actionable genotypes (variants). We assessed the relationship between these genotypes and life span and further examined the specific causes of death among carriers., Results: Through manual curation of 4405 sequence variants in the ACMG SF v3.0 genes, we identified 235 actionable genotypes in 53 genes. Of the 57,933 participants, 2306 (4.0%) carried at least one actionable genotype. We found shorter median survival among persons carrying actionable genotypes than among noncarriers. Specifically, we found that carrying an actionable genotype in a cancer gene was associated with survival that was 3 years shorter than that among noncarriers, with causes of death among carriers attributed primarily to cancer-related conditions. Furthermore, we found evidence of association between carrying an actionable genotype in certain genes in the cardiovascular disease group and a reduced life span., Conclusions: On the basis of the ACMG SF v3.0 guidelines, we found that approximately 1 in 25 Icelanders carried an actionable genotype and that carrying such a genotype was associated with a reduced life span. (Funded by deCODE Genetics-Amgen.)., (Copyright © 2023 Massachusetts Medical Society.)

Objective: The clinical significance of immunohistochemistry (IHC) for unilateral primary aldosteronism (PA) has been unclear. Individualized follow-up of PA patients could be in sight. Long-term outcomes of patients, classified based on IHC, need further investigation. We aimed to assess long-term clinical outcomes for unilateral PA, classifying patients based on IHC., Design: A nationwide observational study, with up to 16 years follow-up, executed in 2007-2016 at Landspitali University Hospital, tertiary referral center. Patients were diagnosed and treated in line with the current guidelines. Haematoxylin and eosin (H&E) tissue slides were stained using CYP11B1 and -B2 antibodies. All cases were re-evaluated and classified according to the HISTALDO consensus. Outcomes were assessed using the PASO criteria., Patients: All unilateral PA patients diagnosed in 2007-2016 in Iceland, 26 patients aged 28-73 years, who underwent adrenalectomy, were included., Measurements: Aldosterone, renin, and cortisol values, use and dosage of antihypertensives, potassium supplementation, blood pressure and serum potassium pre-intervention and throughout follow-up, and histopathology results post-adrenalectomy., Results: Following IHC, an aldosterone-producing nodule was seen in 12 adrenals, an aldosterone-producing adenoma in 10 and multiple aldosterone-producing micronodules in four. IHC altered histopathology from previous H&E diagnosis in 23% (6/26) of the patients. In total, 81% (21/26) of the patients had partial clinical success. Eight percent (2/26) of the patients needed potassium supplementation during follow-up. In the classical group, the AVS results were more determinative with significantly higher lateralization index (median 10.1 vs. 5.3, p = .04) and more contralateral suppression (median nondominant ratio 0.4 vs. 1.0, p = .03). One out of five patients with complete clinical success at 12 months post-op had severe relapse later, the other four were normotensive without antihypertensives for up to 10 years., Conclusions: We found IHC mandatory for accurate histopathologic diagnosis of PA. Our results support the importance of contralateral suppression when interpreting AVS results. Also, the study highlights the complicated assessment of clinical outcome and importance of aldosterone and renin measurements during follow-up., (© 2023 John Wiley & Sons Ltd.)

Background: Persistent symptoms are common after SARS-CoV-2 infection but correlation with objective measures is unclear., Methods: We invited all 3098 adults who tested SARS-CoV-2 positive in Iceland before October 2020 to the deCODE Health Study. We compared multiple symptoms and physical measures between 1706 Icelanders with confirmed prior infection (cases) who participated, and 619 contemporary and 13,779 historical controls. Cases participated in the study 5-18 months after infection., Results: Here we report that 41 of 88 symptoms are associated with prior infection, most significantly disturbed smell and taste, memory disturbance, and dyspnea. Measured objectively, cases had poorer smell and taste results, less grip strength, and poorer memory recall. Differences in grip strength and memory recall were small. No other objective measure associated with prior infection including heart rate, blood pressure, postural orthostatic tachycardia, oxygen saturation, exercise tolerance, hearing, and traditional inflammatory, cardiac, liver, and kidney blood biomarkers. There was no evidence of more anxiety or depression among cases. We estimate the prevalence of long Covid to be 7% at a median of 8 months after infection., Conclusions: We confirm that diverse symptoms are common months after SARS-CoV-2 infection but find few differences between cases and controls in objective parameters measured. These discrepancies between symptoms and physical measures suggest a more complicated contribution to symptoms related to prior infection than is captured with conventional tests. Traditional clinical assessment is not expected to be particularly informative in relating symptoms to a past SARS-CoV-2 infection., (© 2023. The Author(s).)

We present near-field radio holography measurements of the Simons Observatory Large Aperture Telescope Receiver optics. These measurements demonstrate that radio holography of complex millimeter-wave optical systems comprising cryogenic lenses, filters, and feed horns can provide detailed characterization of wave propagation before deployment. We used the measured amplitude and phase, at 4 K, of the receiver near-field beam pattern to predict two key performance parameters: 1) the amount of scattered light that will spill past the telescope to 300 K and 2) the beam pattern expected from the receiver when fielded on the telescope. These cryogenic measurements informed the removal of a filter, which led to improved optical efficiency and reduced sidelobes at the exit of the receiver. Holography measurements of this system suggest that the spilled power past the telescope mirrors will be less than 1%, and the main beam with its near sidelobes are consistent with the nominal telescope design. This is the first time such parameters have been confirmed in the lab prior to deployment of a new receiver. This approach is broadly applicable to millimeter and submillimeter instruments.

Study Question: Does supplementation with vaginal tablets of progesterone after frozen-thawed embryo transfer in natural cycles improve the live birth rate?, Summary Answer: Supplementation with vaginal tablets of progesterone after frozen-thawed embryo transfer in natural cycles significantly improves the number of live births., What Is Known Already: Progesterone supplementation during luteal phase and early pregnancy may improve the number of live births after frozen-thawed embryo transfer. However, due to the limited number of previous studies, being mainly retrospective, evidence is still limited., Study Design, Size, Duration: This is a prospective randomized controlled trial, performed at two university clinics. In total, 500 subjects were randomized with a 1:1 allocation into two groups, during the period February 2013 to March 2018. Randomization was performed after a frozen embryo transfer in a natural cycle by use of opaque sealed envelopes. The primary outcome was live birth rate; secondary outcomes were pregnancy, biochemical pregnancy, clinical pregnancy and miscarriage rate, and if there was a possible association between the serum progesterone concentration on the day of embryo transfer and live birth rate., Participants/materials, Setting, Methods: Women, receiving embryo transfer in natural cycles participated in the study. The embryos were frozen on Day 2, 3, 5 or 6. In total, 672 women having regular menstrual cycles were invited to participate in the study; of those, 500 agreed to participate and 488 were finally included in the study. Half of the study subjects received progesterone supplementation with progesterone vaginal tablets, 100 mg twice daily, starting from the day of embryo transfer. The other half of the subjects were not given any treatment. Blood samples for serum progesterone measurements were collected from all subjects on the day of embryo transfer., Main Results and the Role of Chance: There were no differences in background characteristics between the study groups. In the progesterone supplemented group, 83 of 243 patients (34.2%) had a live birth, compared to 59 of 245 patients (24.1%) in the control group (odds ratio 1.635, 95% CI 1.102-2.428, P = 0.017*). The number of pregnancies was 104 of 243 (42.8%) and 83 of 245 (33.9%), respectively (odds ratio 1.465, 95% CI 1.012-2.108, P = 0.049*) and the number of clinical pregnancies was 91 of 243 (37.4%) and 70 of 245 (28.6%), respectively (odds ratio 1.497, 95% CI 1.024-2.188, P = 0.043*). There were no significant differences in biochemical pregnancy rate or miscarriage rate. There was no correlation between outcome and serum progesterone concentration., Limitations, Reasons for Caution: The study was not blinded because placebo tablets were not available. Supplementation started on embryo transfer day, regardless of the age of the embryos, which resulted in a shorter supplementation time for Day 5/6 embryos compared to Day 2/3 embryos., Wider Implications of the Findings: Supplementation with progesterone in natural cycles improved the number of live births after frozen-thawed embryo transfer and should therefore be considered for introduction in clinical routine., Study Funding/competing Interest(s): The study was funded by Uppsala University, the Uppsala-Family Planning Foundation, and Ferring Pharmaceuticals AB, Malmö, Sweden. The authors have no personal conflicting interests to declare., Trial Registration Number: NL4152., Trial Registration Date: 5 December 2013., Date of First Patient’s Enrolment: 18 February 2013., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Background: Long-term follow-up studies on primary aldosteronism (PA) are lacking., Objective: We aim to review results of diagnostic procedures and histopathology for patients diagnosed during 2012-2016 in Iceland, compare unilateral (UD) and bilateral disease (BD) and assess treatment response., Methods: Thirty-two patients aged 28-88 were diagnosed and treated according to guidelines., Results: The majority had BD. Everyone needed potassium supplementation at case detection. We saw a reduction in systolic blood pressure ( p < .001, both groups), antihypertensive agents ( p = .002 UD and p = .04 BD) and potassium supplementation ( p < .001, both groups)., Conclusion: Similar treatment response was seen in both subgroups. Ratio of hypokalemia and number of cases indicates severe PA underdiagnosis in Iceland.

Study Question: What characterizes the group of donor-conceived (DC) individuals who request information about their identity-release sperm donor in Sweden, and what are their experiences of disclosure, information receipt and donor contact?, Summary Answer: Following three decades of identity-release donation in Sweden, few DC individuals have requested donor information with varying experiences of information receipt and donor contact., What Is Known Already: In 1985, Sweden was the first country worldwide to enact legislation that gave DC individuals the right to obtain identifying information about their donor. Since then, identity-release gamete donation has become available in many countries but there is limited knowledge about the individuals who request donor information., Study Design, Size, Duration: A nation-wide cross-sectional survey study was performed at all seven University hospitals that provided donation treatment in Sweden during 1985-2002. During this period only donor insemination to heterosexual couples was permitted. Inclusion criteria were being 18 years of age or older, conceived with donor sperm and having requested information about the donor by December 2020. Recruitment was performed during 2016-2020., Participants/materials, Setting, Methods: A total of 60 individuals had requested information about their donor. Of these, 53 were approached and 40 individuals, representing 34 families, accepted study participation (75% response rate). Participants completed a postal survey with the WHO-10 well-being index and study-specific questions about experiences of disclosure, motivations for requesting donor information, receipt of information, as well as intentions and experiences of donor contact. Independent t-test and chi-square tests were used to compare ratings of participants with early and late disclosure., Main Results and Role of Chance: Of ∼900 DC individuals who had reached adult age, a total of 60 (≈7%) had requested information about the donor. Most of the 40 study participants (78%) made their requests within 2 years after reaching 18 years of age, or following disclosure at later ages (up to 32 years). Several participants had adult DC siblings in the family who had not requested any donor information. All except five participants received identifying information about the donor from the clinic. However, some donors had died or lacked contact information. Among those participants who were able to contact their donor, 41% had done so at the time of the study, while a third of the participants were unsure about potential contact. Several had met the donor in person and a few were in regular contact. About half of the participants had been informed about their donor conception in adolescence or adulthood (age 12-32), and there were significant differences between participants based on age at disclosure. Compared to those with early disclosure, participants with late disclosure were significantly more likely to be dissatisfied with the timing of their disclosure (P = 0.021), to react with negative emotions (P < 0.001), and to subsequently contact the donor (P = 0.047)., Limitations, Reasons for Caution: The limited population available for inclusion resulted in a small sample size, despite a high response rate. In addition, men's lower participation rate must be taken into consideration when interpreting the results., Wider Implications of the Findings: The small number of individuals requesting information about their identity-release sperm donor is surprising. While not all DC individuals appear to be interested in donor information, it is reasonable to assume that some are unaware of their donor conception and thus unable to make informed decisions regarding their genetic origins. During the coming years, young women and men in many countries will become eligible to access identifying information about their donor. In order to meet the needs of these individuals, and to support positive outcomes for all involved parties, it is essential that adequate protocols and resources are developed., Study Funding/competing Interest: Financial support from The Swedish Research Council. There are no conflicts of interest to declare., Trial Registration Number: N/A., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Near-field radio holography is a common method for measuring and aligning mirror surfaces for millimeter and sub-millimeter telescopes. In instruments with more than a single mirror, degeneracies arise in the holography measurement, requiring multiple measurements and new fitting methods. We present HoloSim-ML, a Python code for beam simulation and analysis of radio holography data from complex optical systems. This code uses machine learning to efficiently determine the position of hundreds of mirror adjusters on multiple mirrors with few micrometer accuracy. We apply this approach to the example of the Simons Observatory 6 m telescope.

Platelets play an important role in hemostasis and other aspects of vascular biology. We conducted a meta-analysis of platelet count GWAS using data on 536,974 Europeans and identified 577 independent associations. To search for mechanisms through which these variants affect platelets, we applied cis-expression quantitative trait locus, DEPICT and IPA analyses and assessed genetic sharing between platelet count and various traits using polygenic risk scoring. We found genetic sharing between platelet count and counts of other blood cells (except red blood cells), in addition to several other quantitative traits, including markers of cardiovascular, liver and kidney functions, height, and weight. Platelet count polygenic risk score was predictive of myeloproliferative neoplasms, rheumatoid arthritis, ankylosing spondylitis, hypertension, and benign prostate hyperplasia. Taken together, these results advance understanding of diverse aspects of platelet biology and how they affect biological processes in health and disease., (© 2021. The Author(s).)

The success of genome-wide association studies (GWAS) in identifying common, low-penetrance variant-cancer associations for the past decade is undisputed. However, discovering additional high-penetrance cancer mutations in unknown cancer predisposing genes requires detection of variant-cancer association of ultra-rare coding variants. Consequently, large-scale next-generation sequence data with associated phenotype information are needed. Here, we used genotype data on 166,281 Icelanders, of which, 49,708 were whole-genome sequenced and 408,595 individuals from the UK Biobank, of which, 41,147 were whole-exome sequenced, to test for association between loss-of-function burden in autosomal genes and basal cell carcinoma (BCC), the most common cancer in Caucasians. A total of 25,205 BCC cases and 683,058 controls were tested. Rare germline loss-of-function variants in PTPN14 conferred substantial risks of BCC (OR, 8.0; P = 1.9 × 10 -12 ), with a quarter of carriers getting BCC before age 70 and over half in their lifetime. Furthermore, common variants at the PTPN14 locus were associated with BCC, suggesting PTPN14 as a new, high-impact BCC predisposition gene. A follow-up investigation of 24 cancers and three benign tumor types showed that PTPN14 loss-of-function variants are associated with high risk of cervical cancer (OR, 12.7, P = 1.6 × 10 -4 ) and low age at diagnosis. Our findings, using power-increasing methods with high-quality rare variant genotypes, highlight future prospects for new discoveries on carcinogenesis. SIGNIFICANCE: This study identifies the tumor-suppressor gene PTPN14 as a high-impact BCC predisposition gene and indicates that inactivation of PTPN14 by germline sequence variants may also lead to increased risk of cervical cancer., (©2021 American Association for Cancer Research.)

Thyroid stimulating hormone (TSH) is critical for normal development and metabolism. To better understand the genetic contribution to TSH levels, we conduct a GWAS meta-analysis at 22.4 million genetic markers in up to 119,715 individuals and identify 74 genome-wide significant loci for TSH, of which 28 are previously unreported. Functional experiments show that the thyroglobulin protein-altering variants P118L and G67S impact thyroglobulin secretion. Phenome-wide association analysis in the UK Biobank demonstrates the pleiotropic effects of TSH-associated variants and a polygenic score for higher TSH levels is associated with a reduced risk of thyroid cancer in the UK Biobank and three other independent studies. Two-sample Mendelian randomization using TSH index variants as instrumental variables suggests a protective effect of higher TSH levels (indicating lower thyroid function) on risk of thyroid cancer and goiter. Our findings highlight the pleiotropic effects of TSH-associated variants on thyroid function and growth of malignant and benign thyroid tumors.

Autoimmune thyroid disease is the most common autoimmune disease and is highly heritable 1 . Here, by using a genome-wide association study of 30,234 cases and 725,172 controls from Iceland and the UK Biobank, we find 99 sequence variants at 93 loci, of which 84 variants are previously unreported 2-7 . A low-frequency (1.36%) intronic variant in FLT3 (rs76428106-C) has the largest effect on risk of autoimmune thyroid disease (odds ratio (OR) = 1.46, P = 2.37 × 10 -24 ). rs76428106-C is also associated with systemic lupus erythematosus (OR = 1.90, P = 6.46 × 10 -4 ), rheumatoid factor and/or anti-CCP-positive rheumatoid arthritis (OR = 1.41, P = 4.31 × 10 -4 ) and coeliac disease (OR = 1.62, P = 1.20 × 10 -4 ). FLT3 encodes fms-related tyrosine kinase 3, a receptor that regulates haematopoietic progenitor and dendritic cells. RNA sequencing revealed that rs76428106-C generates a cryptic splice site, which introduces a stop codon in 30% of transcripts that are predicted to encode a truncated protein, which lacks its tyrosine kinase domains. Each copy of rs76428106-C doubles the plasma levels of the FTL3 ligand. Activating somatic mutations in FLT3 are associated with acute myeloid leukaemia 8 with a poor prognosis and rs76428106-C also predisposes individuals to acute myeloid leukaemia (OR = 1.90, P = 5.40 × 10 -3 ). Thus, a predicted loss-of-function germline mutation in FLT3 causes a reduction in full-length FLT3, with a compensatory increase in the levels of its ligand and an increased disease risk, similar to that of a gain-of-function mutation.

Genome-wide association studies (GWASs) have identified at least 10 single-nucleotide polymorphisms (SNPs) associated with papillary thyroid cancer (PTC) risk. Most of these SNPs are common variants with small to moderate effect sizes. Here we assessed the combined genetic effects of these variants on PTC risk by using summarized GWAS results to build polygenic risk score (PRS) models in three PTC study groups from Ohio (1,544 patients and 1,593 controls), Iceland (723 patients and 129,556 controls), and the United Kingdom (534 patients and 407,945 controls). A PRS based on the 10 established PTC SNPs showed a stronger predictive power compared with the clinical factors model, with a minimum increase of area under the receiver-operating curve of 5.4 percentage points ( P ≤ 1.0 × 10 -9 ). Adding an extended PRS based on 592,475 common variants did not significantly improve the prediction power compared with the 10-SNP model, suggesting that most of the remaining undiscovered genetic risk in thyroid cancer is due to rare, moderate- to high-penetrance variants rather than to common low-penetrance variants. Based on the 10-SNP PRS, individuals in the top decile group of PRSs have a close to sevenfold greater risk (95% CI, 5.4-8.8) compared with the bottom decile group. In conclusion, PRSs based on a small number of common germline variants emphasize the importance of heritable low-penetrance markers in PTC., Competing Interests: Competing interest statement: J.G., E.F., V.T., G.T., and K.S. are employees of deCODE/Amgen. The other authors have no conflicts of interest to declare.

Pelvic organ prolapse (POP) is a downward descent of one or more of the pelvic organs, resulting in a protrusion of the vaginal wall and/or uterus. We performed a genome-wide association study of POP using data from Iceland and the UK Biobank, a total of 15,010 cases with hospital-based diagnosis code and 340,734 female controls, and found eight sequence variants at seven loci associating with POP (P < 5 × 10 -8 ); seven common (minor allele frequency >5%) and one with minor allele frequency of 4.87%. Some of the variants associating with POP also associated with traits of similar pathophysiology. Of these, rs3820282, which may alter the estrogen-based regulation of WNT4, also associates with leiomyoma of uterus, gestational duration and endometriosis. Rs3791675 at EFEMP1, a gene involved in connective tissue homeostasis, also associates with hernias and carpal tunnel syndrome. Our results highlight the role of connective tissue metabolism and estrogen exposure in the etiology of POP.

Background: Alpha-fetoprotein (AFP), cancer antigens 15.3, 19.9, and 125, carcinoembryonic antigen, and alkaline phosphatase (ALP) are widely measured in attempts to detect cancer and to monitor treatment response. However, due to lack of sensitivity and specificity, their utility is debated. The serum levels of these markers are affected by a number of nonmalignant factors, including genotype. Thus, it may be possible to improve both sensitivity and specificity by adjusting test results for genetic effects., Methods: We performed genome-wide association studies of serum levels of AFP ( N = 22,686), carcinoembryonic antigen ( N = 22,309), cancer antigens 15.3 ( N = 7,107), 19.9 ( N = 9,945), and 125 ( N = 9,824), and ALP ( N = 162,774). We also examined the correlations between levels of these biomarkers and the presence of cancer, using data from a nationwide cancer registry., Results: We report a total of 84 associations of 79 sequence variants with levels of the six biomarkers, explaining between 2.3% and 42.3% of the phenotypic variance. Among the 79 variants, 22 are cis (in- or near the gene encoding the biomarker), 18 have minor allele frequency less than 1%, 31 are coding variants, and 7 are associated with gene expression in whole blood. We also find multiple conditions associated with higher biomarker levels., Conclusions: Our results provide insights into the genetic contribution to diversity in concentration of tumor biomarkers in blood., Impact: Genetic correction of biomarker values could improve prediction algorithms and decision-making based on these biomarkers., (©2019 American Association for Cancer Research.)

MicroRNAs (miRNAs) can provide insight into the pathophysiological states of ocular tissues such as proliferative diabetic retinopathy (PDR). In this study, differences in miRNA expression in vitreous from PDR patients with and without incidence of recurrent vitreous hemorrhage (RVH) after the initial pars-plana vitrectomy (PPV) were analyzed, with the aim of identifying biomarkers for RVH. Fifty-four consented vitreous samples were analyzed from patients undergoing PPV for PDR, of which eighteen samples underwent a second surgery due to RVH. Ten of the sixty-six expressed miRNAs (miRNAs-19a, -20a, -22, -27a, -29a, -93, -126, -128, -130a, and -150) displayed divergences between the PDR vitreous groups and to the control. A significant increase in the miRNA-19a and -27a expression was determined in PDR patients undergoing PPV as compared to the controls. miRNA-20a and -93 were significantly upregulated in primary PPV vitreous samples of patients afflicted with RVH. Moreover, this observed upregulation was not significant between the non-RVH and control group, thus emphasizing the association with RVH incidence. miRNA-19a and -27a were detected as putative vitreous biomarkers for PDR, and elevated levels of miRNA-20a and -93 in vitreous with RVH suggest their biomarker potential for major PDR complications such as recurrent hemorrhage incidence.

Benign prostatic hyperplasia and associated lower urinary tract symptoms (BPH/LUTS) are common conditions affecting the majority of elderly males. Here we report the results of a genome-wide association study of symptomatic BPH/LUTS in 20,621 patients and 280,541 controls of European ancestry, from Iceland and the UK. We discovered 23 genome-wide significant variants, located at 14 loci. There is little or no overlap between the BPH/LUTS variants and published prostate cancer risk variants. However, 15 of the variants reported here also associate with serum levels of prostate specific antigen (PSA) (at a Bonferroni corrected P < 0.0022). Furthermore, there is a strong genetic correlation, r g  = 0.77 (P = 2.6 × 10 -11 ), between PSA and BPH/LUTS, and one standard deviation increase in a polygenic risk score (PRS) for BPH/LUTS increases PSA levels by 12.9% (P = 1.6×10 -55 ). These results shed a light on the genetic background of BPH/LUTS and its substantial influence on PSA levels.