Genomic analysis of male puberty timing highlights shared genetic basis with hair colour and lifespan

The timing of puberty is highly variable and is associated with long-term health outcomes. To date, understanding of the genetic control of puberty timing is based largely on studies in women. Here, we report a multi-trait genome-wide association study for male puberty timing with an effective sample size of 205,354 men. We find moderately strong genomic correlation in puberty timing between sexes (rg = 0.68) and identify 76 independent signals for male puberty timing. Implicated mechanisms include an unexpected link between puberty timing and natural hair colour, possibly reflecting common effects of pituitary hormones on puberty and pigmentation. Earlier male puberty timing is genetically correlated with several adverse health outcomes and Mendelian randomization analyses show a genetic association between male puberty timing and shorter lifespan. These findings highlight the relationships between puberty timing and health outcomes, and demonstrate the value of genetic studies of puberty timing in both sexes

Genomic analysis of male puberty timing highlights shared genetic basis with hair colour and lifespan

The timing of puberty is highly variable and is associated with long-term health outcomes. To date, understanding of the genetic control of puberty timing is based largely on studies in women. Here, we report a multi-trait genome-wide association study for male puberty timing with an effective sample size of 205,354 men. We find moderately strong genomic correlation in puberty timing between sexes (rg = 0.68) and identify 76 independent signals for male puberty timing. Implicated mechanisms include an unexpected link between puberty timing and natural hair colour, possibly reflecting common effects of pituitary hormones on puberty and pigmentation. Earlier male puberty timing is genetically correlated with several adverse health outcomes and Mendelian randomization analyses show a genetic association between male puberty timing and shorter lifespan. These findings highlight the relationships between puberty timing and health outcomes, and demonstrate the value of genetic studies of puberty timing in both sexes

Genome-wide association study of anti-Müllerian hormone levels in pre-menopausal women of late reproductive age and relationship with genetic determinants of reproductive lifespan

This is the author accepted manuscript. The final version is available from Oxford University Press via the DOI in this record.Anti-Müllerian hormone (AMH) is required for sexual differentiation in the fetus, and in adult females AMH is produced by growing ovarian follicles. Consequently, AMH levels are correlated with ovarian reserve, declining towards menopause when the oocyte pool is exhausted. A previous genome-wide association study identified three genetic variants in and around the AMH gene that explained 25% of variation in AMH levels in adolescent males but did not identify any genetic associations reaching genome-wide significance in adolescent females. To explore the role of genetic variation in determining AMH levels in women of late reproductive age, we carried out a genome-wide meta-analysis in 3,344 pre-menopausal women from five cohorts (median age 44–48 years at blood draw). A single genetic variant, rs16991615, previously associated with age at menopause, reached genome-wide significance at P=3.48×10-10, with a per allele difference in age-adjusted inverse normal AMH of 0.26 SD (95% CI [0.18,0.34]). We investigated whether genetic determinants of female reproductive lifespan were more generally associated with pre-menopausal AMH levels. Genetically-predicted age at menarche had no robust association but genetically-predicted age at menopause was associated with lower AMH levels by 0.18 SD (95% CI [0.14,0.21]) in age-adjusted inverse normal AMH per one-year earlier age at menopause. Our findings provide genetic support for the well-established use of AMH as a marker of ovarian reserve.Breast Cancer NowInstitute of Cancer Researc

The genetic architecture of sporadic and multiple consecutive miscarriage

Miscarriage is a common, complex trait affecting ~15% of clinically confirmed pregnancies. Here we present the results of large-scale genetic association analyses with 69,054 cases from five different ancestries for sporadic miscarriage, 750 cases of European ancestry for multiple (≥3) consecutive miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association (rs146350366, minor allele frequency (MAF) 1.2%, P = 3.2 × 10−8, odds ratio (OR) = 1.4) for sporadic miscarriage in our European ancestry meta-analysis and three genome-wide significant associations for multiple consecutive miscarriage (rs7859844, MAF = 6.4%, P = 1.3 × 10−8, OR = 1.7; rs143445068, MAF = 0.8%, P = 5.2 × 10−9, OR = 3.4; rs183453668, MAF = 0.5%, P = 2.8 × 10−8, OR = 3.8). We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability, and genetic correlation analyses. Our results show that miscarriage etiopathogenesis is partly driven by genetic variation potentially related to placental biology, and illustrate the utility of large-scale biobank data for understanding this pregnancy complication

Genome-wide association study of anti-Müllerian hormone levels in pre-menopausal women of late reproductive age and relationship with genetic determinants of reproductive lifespan

This is the author accepted manuscript. The final version is available from Oxford University Press via the DOI in this record.Anti-Müllerian hormone (AMH) is required for sexual differentiation in the fetus, and in adult females AMH is produced by growing ovarian follicles. Consequently, AMH levels are correlated with ovarian reserve, declining towards menopause when the oocyte pool is exhausted. A previous genome-wide association study identified three genetic variants in and around the AMH gene that explained 25% of variation in AMH levels in adolescent males but did not identify any genetic associations reaching genome-wide significance in adolescent females. To explore the role of genetic variation in determining AMH levels in women of late reproductive age, we carried out a genome-wide meta-analysis in 3,344 pre-menopausal women from five cohorts (median age 44–48 years at blood draw). A single genetic variant, rs16991615, previously associated with age at menopause, reached genome-wide significance at P=3.48×10-10, with a per allele difference in age-adjusted inverse normal AMH of 0.26 SD (95% CI [0.18,0.34]). We investigated whether genetic determinants of female reproductive lifespan were more generally associated with pre-menopausal AMH levels. Genetically-predicted age at menarche had no robust association but genetically-predicted age at menopause was associated with lower AMH levels by 0.18 SD (95% CI [0.14,0.21]) in age-adjusted inverse normal AMH per one-year earlier age at menopause. Our findings provide genetic support for the well-established use of AMH as a marker of ovarian reserve.Breast Cancer NowInstitute of Cancer Researc

A sobrecarga do familiar cuidador no âmbito domiciliar: uma revisão integrativa da literatura La sobrecarga del familiar cuidador en el entorno domiciliario: una revisión de la literatura Overload of family caregiver at home: an integrative literature review

Trata-se de uma revisão integrativa de literatura que teve como objetivo identificar as evidências acerca dos fatores geradores de sobrecarga e suas consequências para os familiares cuidadores de adultos ou idosos. A revisão abrangeu 27 estudos em base de dados, com as palavras-chave cuidadores, família e sobrecarga, no período de 1999 a 2009. Foram desveladas quatro categorias: a imposição de ser o cuidador, o cuidar solitário, a dependência do ser cuidado e o desgaste biopsicossocial do cuidador. Os resultados demonstram que a imposição do papel de cuidador, a falta de apoio dos outros familiares, o grau de dependência do enfermo relacionada à patologia, e o desgaste físico e psicológico são os principais fatores geradores de sobrecarga dos familiares cuidadores. Verifica-se a necessidade de maior suporte dos profissionais de saúde no sentido de apoiar e estar disponível aos familiares cuidadores nas intercorrências das atividades cuidativas no domicílio.<br>Se trata de una revisión integradora de la literatura dirigida a identificar la evidencia de los factores que causan sobrecarga y sus consecuencias para los familiares cuidadores de adultos o ancianos. La revisión abarcó 27 estudios en base de datos con los descriptores cuidadores, familia y sobrecarga, de 1999 a 2009. Cuatro categorías se desvelaron: la imposición de ser el cuidador, el cuidado solitario, la dependencia del ser cuidado y el desgaste biopsicosocial del cuidador. Los resultados muestran que la imposición del rol de cuidador, la falta de apoyo de otros familiares, el grado de dependencia del enfermo relacionado con la patología y el desgaste físico y psicológico son los principales factores generadores de sobrecarga de familiares cuidadores. Se constata la necesidad de mayor soporte de profesionales de la salud para apoyar y estar a disposición de los familiares cuidadores en las complicaciones de las actividades cuidadoras en hogar.<br>This is an integrative literature review that aims to identify evidences on the factors causing overload and their consequences for family caregivers of adults or the elderly. The review covered 27 studies at databases, using the keywords caregivers, family, and overload, in the period from 1999 to 2009. Four categories came up: the imposition of being a caregiver, taking care alone, the dependence of the person that receives care, and the bio-psychosocial weariness of the caregiver. The results showed that the imposition of the role of caregiver, lack of support from other family members, level of dependency of the patient related to the pathology, and physical and psychological weariness are the main factors causing overload in family caregivers. The need for more support and availability by health professionals to family caregivers in their home activities is evident