Genome-wide association study for incident myocardial infarction and coronary heart disease in prospective cohort studies: The CHARGE Consortium

Background Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting. Methods We performed a two-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5×10−6 in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with total mortality in individuals who experienced MI during follow-up. Results In Stage I 15 loci passed the threshold of 5×10−6; 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value<8.8×10−3) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2×10−9). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2×10−3). Conclusions QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders

Southern Ocean carbon sink enhanced by sea-ice feedbacks at the Antarctic Cold Reversal

The Southern Ocean occupies 14% of the Earth’s surface and plays a fundamental role in the global carbon cycle and climate. It provides a direct connection to the deep ocean carbon reservoir through biogeochemical processes that include surface primary productivity, remineralization at depth and the upwelling of carbon-rich water masses. However, the role of these different processes in modulating past and future air–sea carbon flux remains poorly understood. A key period in this regard is the Antarctic Cold Reversal (ACR, 14.6–12.7 kyr bp), when mid- to high-latitude Southern Hemisphere cooling coincided with a sustained plateau in the global deglacial increase in atmospheric CO2. Here we reconstruct high-latitude Southern Ocean surface productivity from marine-derived aerosols captured in a highly resolved horizontal ice core. Our multiproxy reconstruction reveals a sustained signal of enhanced marine productivity across the ACR. Transient climate modelling indicates this period coincided with maximum seasonal variability in sea-ice extent, implying that sea-ice biological feedbacks enhanced CO2 sequestration and created a substantial regional marine carbon sink, which contributed to the plateau in CO2 during the ACR. Our results highlight the role Antarctic sea ice plays in controlling global CO2, and demonstrate the need to incorporate such feedbacks into climate–carbon models

A Genome-Wide Association Meta-Analysis of Circulating Sex Hormone-Binding Globulin Reveals Multiple Loci Implicated in Sex Steroid Hormone Regulation

Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8x10(-106)), PRMT6 (rs17496332, 1p13.3, p=1.4x10(-11)), GCKR (rs780093, 2p23.3, p=2.2x10(-16)), ZBTB10 (rs440837, 8q21.13, p=3.4x10(-09)), JMJD1C (rs7910927, 10q21.3, p=6.1x10(-35)), SLCO1B1 (rs4149056, 12p12.1, p=1.9x10(-08)), NR2F2 (rs8023580, 15q26.2, p=8.3x10(-12)), ZNF652 (rs2411984, 17q21.32, p=3.5x10(-14)), TDGF3 (rs1573036, Xq22.3, p=4.1x10(-14)), LHCGR (rs10454142, 2p16.3, p=1.3x10(-07)), BAIAP2L1 (rs3779195, 7q21.3, p=2.7x10(-08)), and UGT2B15 (rs293428, 4q13.2, p=5.5x10(-06)). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p = 2.5x10(-08), women p=0.66, heterogeneity p=0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained similar to 15.6% and similar to 8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance

Neural Regulation of Paternal Behavior in Mammals: Sensory, Neuroendocrine, and Experiential Influences on the Paternal Brain.

Across the animal kingdom, parents in many species devote extraordinary effort toward caring for offspring, often risking their lives and exhausting limited resources. Understanding how the brain orchestrates parental care, biasing effort over the many competing demands, is an important topic in social neuroscience. In mammals, maternal care is necessary for offspring survival and is largely mediated by changes in hormones and neuropeptides that fluctuate massively during pregnancy, parturition, and lactation (e.g., progesterone, estradiol, oxytocin, and prolactin). In the relatively small number of mammalian species in which parental care by fathers enhances offspring survival and development, males also undergo endocrine changes concurrent with birth of their offspring, but on a smaller scale than females. Thus, fathers additionally rely on sensory signals from their mates, environment, and/or offspring to orchestrate paternal behavior. Males can engage in a variety of infant-directed behaviors that range from infanticide to avoidance to care; in many species, males can display all three behaviors in their lifetime. The neural plasticity that underlies such stark changes in behavior is not well understood. In this chapter we summarize current data on the neural circuitry that has been proposed to underlie paternal care in mammals, as well as sensory, neuroendocrine, and experiential influences on paternal behavior and on the underlying circuitry. We highlight some of the gaps in our current knowledge of this system and propose future directions that will enable the development of a more comprehensive understanding of the proximate control of parenting by fathers