Background

Insulin-like growth factor 1 (IGF-1) signaling has been implicated in Alzheimer's disease pathogenesis, and further evidence suggests inflammation can be a moderator of this association. However, most research to date has been conducted on older adults.

Objective

To investigate the association of serum IGF-1 and IGF binding protein 3 (IGFBP-3) concentrations with MRI markers of Alzheimer's disease in predominantly middle-aged adults, and further assess moderation by chronic inflammation.

Methods

We included participants from the Framingham Heart Study (n = 1,852, mean age 46±8, 46% men) and the Study of Health in Pomerania (n = 674, mean age 50±13, 42% men) with available serum IGF-1, IFGBP-3, as well as brain MRI. IGF-1 and IFGBP-3 were related to MRI outcomes (i.e., total brain, cortical gray matter, white matter, white matter hyperintensities (WMH), and hippocampal volumes) using multivariable regression models adjusting for potential confounders. Subgroup analyses by C-reactive protein (CRP) concentrations were also performed. Cohort-specific summary statistics were meta-analyzed using random-effects models and corrected for multiple comparisons.

Results

Meta-analysis results revealed that higher IGF-1 concentrations were associated with lower WMH (estimate [β] [95% CI], -0.05 [-0.09, -0.02], p = 0.006) and larger hippocampal volumes (0.07 [0.02, 0.12], p = 0.01), independent of vascular risk factors. These associations occurred predominantly in individuals with CRP concentrations < 75th percentile. We did not observe associations between IGFBP-3 and MRI outcomes.

Conclusion

Our findings suggest that IGF-1-related signaling may be implicated in brain health as early as midlife.

One of the features that distinguishes modern humans from our extinct relatives and ancestors is a globular shape of the braincase [1-4]. As the endocranium closely mirrors the outer shape of the brain, these differences might reflect altered neural architecture [4, 5]. However, in the absence of fossil brain tissue, the underlying neuroanatomical changes as well as their genetic bases remain elusive. To better understand the biological foundations of modern human endocranial shape, we turn to our closest extinct relatives: the Neandertals. Interbreeding between modern humans and Neandertals has resulted in introgressed fragments of Neandertal DNA in the genomes of present-day non-Africans [6, 7]. Based on shape analyses of fossil skull endocasts, we derive a measure of endocranial globularity from structural MRI scans of thousands of modern humans and study the effects of introgressed fragments of Neandertal DNA on this phenotype. We find that Neandertal alleles on chromosomes 1 and 18 are associated with reduced endocranial globularity. These alleles influence expression of two nearby genes, UBR4 and PHLPP1, which are involved in neurogenesis and myelination, respectively. Our findings show how integration of fossil skull data with archaic genomics and neuroimaging can suggest developmental mechanisms that may contribute to the unique modern human endocranial shape.

Background

Circulating lipids and insulin-like growth factor 1 (IGF-I) have been reliably associated with breast cancer. Observational studies suggest an interplay between lipids and IGF-I, however, whether these relationships are causal and if pathways from these phenotypes to breast cancer overlap is unclear.

Methods

Mendelian randomization (MR) was conducted to estimate the relationship between lipids or IGF-I and breast cancer risk using genetic summary statistics for lipids (low-density lipoprotein cholesterol, LDL-C; high-density lipoprotein cholesterol, HDL-C; triglycerides, TGs), IGF-I and breast cancer from GLGC/UKBB (N = 239,119), CHARGE/UKBB (N = 252,547), and Breast Cancer Association Consortium (N = 247,173), respectively. Cross-sectional observational and MR analyses were conducted to assess the bi-directional relationship between lipids and IGF-I in SHIP (N = 3,812) and UKBB (N = 422,389), and using genetic summary statistics from GLGC (N = 188,577) and CHARGE/UKBB (N = 469,872).

Results

In multivariable MR (MVMR) analyses, the OR for breast cancer per 1-SD increase in HDL-C and TG was 1.08 [95% confidence interval (CI), 1.04-1.13] and 0.94 (95% CI, 0.89-0.98), respectively. The OR for breast cancer per 1-SD increase in IGF-I was 1.09 (95% CI, 1.04-1.15). MR analyses suggested a bi-directional TG-IGF-I relationship (TG-IGF-I β per 1-SD: -0.13; 95% CI, -0.23 to -0.04; and IGF-I-TG β per 1-SD: -0.11; 95% CI, -0.18 to -0.05). There was little evidence for a causal relationship between HDL-C and LDL-C with IGF-I. In MVMR analyses, associations of TG or IGF-I with breast cancer were robust to adjustment for IGF-I or TG, respectively.

Conclusions

Our findings suggest a causal role of HDL-C, TG, and IGF-I in breast cancer. Observational and MR analyses support an interplay between IGF-I and TG; however, MVMR estimates suggest that TG and IGF-I may act independently to influence breast cancer.

Impact

Our findings should be considered in the development of prevention strategies for breast cancer, where interventions are known to modify circulating lipids and IGF-I.

Advances in technology enable increasing amounts of data collection from individuals for biomedical research. Such technologies, for example, in genetics and medical imaging, have also led to important scientific discoveries about health and disease. The combination of multiple types of high-throughput data for complex analyses, however, has been limited by analytical and logistic resources to handle high-dimensional data sets. In our previous EU Joint Programme-Neurodegenerative Disease Research (JPND) Working Group, called HD-READY, we developed methods that allowed successful combination of omics data with neuroimaging. Still, several issues remained to fully leverage high-dimensional multimodality data. For instance, high-dimensional features, such as voxels and vertices, which are common in neuroimaging, remain difficult to harmonize. In this Full-HD Working Group, we focused on such harmonization of high-dimensional neuroimaging phenotypes in combination with other omics data and how to make the resulting ultra-high-dimensional data easily accessible in neurodegeneration research.

One of the features that distinguishes modern humans from our extinct relatives and ancestors is a globular shape of the braincase [1-4]. As the endocranium closely mirrors the outer shape of the brain, these differences might reflect altered neural architecture [4, 5]. However, in the absence of fossil brain tissue, the underlying neuroanatomical changes as well as their genetic bases remain elusive. To better understand the biological foundations of modern human endocranial shape, we turn to our closest extinct relatives: the Neandertals. Interbreeding between modern humans and Neandertals has resulted in introgressed fragments of Neandertal DNA in the genomes of present-day non-Africans [6, 7]. Based on shape analyses of fossil skull endocasts, we derive a measure of endocranial globularity from structural MRI scans of thousands of modern humans and study the effects of introgressed fragments of Neandertal DNA on this phenotype. We find that Neandertal alleles on chromosomes 1 and 18 are associated with reduced endocranial globularity. These alleles influence expression of two nearby genes, UBR4 and PHLPP1, which are involved in neurogenesis and myelination, respectively. Our findings show how integration of fossil skull data with archaic genomics and neuroimaging can suggest developmental mechanisms that may contribute to the unique modern human endocranial shape.

Objectives

To identify genetic associations with hip osteoarthritis (HOA), we performed a meta-analysis of genome-wide association studies (GWAS) of HOA.

Methods

The GWAS meta-analysis included approximately 2.5 million imputed HapMap single nucleotide polymorphisms (SNPs). HOA cases and controls defined radiographically and by total hip replacement were selected from the Osteoporotic Fractures in Men (MrOS) Study and the Study of Osteoporotic Fractures (SOF) (654 cases and 4697 controls, combined). Replication of genome-wide significant SNP associations (p ≤5×10(-8)) was examined in five studies (3243 cases and 6891 controls, combined). Functional studies were performed using in vitro models of chondrogenesis and osteogenesis.

Results

The A allele of rs788748, located 65 kb upstream of the IGFBP3 gene, was associated with lower HOA odds at the genome-wide significance level in the discovery stage (OR 0.71, p=2×10(-8)). The association replicated in five studies (OR 0.92, p=0.020), but the joint analysis of discovery and replication results was not genome-wide significant (p=1×10(-6)). In separate study populations, the rs788748 A allele was also associated with lower circulating IGFBP3 protein levels (p=4×10(-13)), suggesting that this SNP or a variant in linkage disequilibrium could be an IGFBP3 regulatory variant. Results from functional studies were consistent with association results. Chondrocyte hypertrophy, a deleterious event in OA pathogenesis, was largely prevented upon IGFBP3 knockdown in chondrocytes. Furthermore, IGFBP3 overexpression induced cartilage catabolism and osteogenic differentiation.

Conclusions

Results from GWAS and functional studies provided suggestive links between IGFBP3 and HOA.

Family studies suggest a genetic component to the etiology of chronic kidney disease (CKD) and end stage renal disease (ESRD). Previously, we identified 16 loci for eGFR in genome-wide association studies, but the associations of these single nucleotide polymorphisms (SNPs) for incident CKD or ESRD are unknown. We thus investigated the association of these loci with incident CKD in 26,308 individuals of European ancestry free of CKD at baseline drawn from eight population-based cohorts followed for a median of 7.2 years (including 2,122 incident CKD cases defined as eGFR <60ml/min/1.73m(2) at follow-up) and with ESRD in four case-control studies in subjects of European ancestry (3,775 cases, 4,577 controls). SNPs at 11 of the 16 loci (UMOD, PRKAG2, ANXA9, DAB2, SHROOM3, DACH1, STC1, SLC34A1, ALMS1/NAT8, UBE2Q2, and GCKR) were associated with incident CKD; p-values ranged from p = 4.1e-9 in UMOD to p = 0.03 in GCKR. After adjusting for baseline eGFR, six of these loci remained significantly associated with incident CKD (UMOD, PRKAG2, ANXA9, DAB2, DACH1, and STC1). SNPs in UMOD (OR = 0.92, p = 0.04) and GCKR (OR = 0.93, p = 0.03) were nominally associated with ESRD. In summary, the majority of eGFR-related loci are either associated or show a strong trend towards association with incident CKD, but have modest associations with ESRD in individuals of European descent. Additional work is required to characterize the association of genetic determinants of CKD and ESRD at different stages of disease progression.

Hypertension represents a major cardiovascular risk factor. The pathophysiology of increased blood pressure (BP) is not yet completely understood. Transcriptome profiling offers possibilities to uncover genetics effects on BP. Based on 2 populations including 2549 individuals, a meta-analyses of monocytic transcriptome-wide profiles were performed to identify transcripts associated with BP. Replication was performed in 2 independent studies of whole-blood transcriptome data including 1990 individuals. For identified candidate genes, a direct link between long-term changes in BP and gene expression over time and by treatment with BP-lowering therapy was assessed. The predictive value of protein levels encoded by candidate genes for subsequent cardiovascular disease was investigated. Eight transcripts (CRIP1, MYADM, TIPARP, TSC22D3, CEBPA, F12, LMNA, and TPPP3) were identified jointly accounting for up to 13% (95% confidence interval, 8.7-16.2) of BP variability. Changes in CRIP1, MYADM, TIPARP, LMNA, TSC22D3, CEBPA, and TPPP3 expression associated with BP changes-among these, CRIP1 gene expression was additionally correlated to measures of cardiac hypertrophy. Assessment of circulating CRIP1 (cystein-rich protein 1) levels as biomarkers showed a strong association with increased risk for incident stroke (hazard ratio, 1.06; 95% confidence interval, 1.03-1.09; P=5.0×10^-5). Our comprehensive analysis of global gene expression highlights 8 novel transcripts significantly associated with BP, providing a link between gene expression and BP. Translational approaches further established evidence for the potential use of CRIP1 as emerging disease-related biomarker.

Background

Epigenome-wide association studies have identified multiple DNA methylation sites (CpGs) associated with alcohol consumption, an important lifestyle risk factor for cardiovascular diseases. This study aimed to test the hypothesis that an alcohol consumption epigenetic risk score (ERS) is associated with blood pressure (BP) traits.

Results

We implemented an ERS based on a previously reported epigenetic signature of 144 alcohol-associated CpGs in meta-analysis of participants of European ancestry. We found a one-unit increment of ERS was associated with eleven drinks of alcohol consumed per day, on average, across several cohorts (p < 0.0001). We examined the association of the ERS with systolic blood pressure (SBP), diastolic blood pressure (DBP), and hypertension (HTN) in 3,898 Framingham Heart Study (FHS) participants. Cross-sectional analyses in FHS revealed that a one-unit increment of the ERS was associated with 1.93 mm Hg higher SBP (p = 4.64E-07), 0.68 mm Hg higher DBP (p = 0.006), and an odds ratio of 1.78 for HTN (p < 2E-16). Meta-analysis of the cross-sectional association of the ERS with BP traits in eight independent external cohorts (n = 11,544) showed similar relationships with BP levels, i.e., a one-unit increase in ERS was associated with 0.74 mm Hg (p = 0.002) higher SBP and 0.50 mm Hg (p = 0.0006) higher DBP, but not with HTN. Longitudinal analyses in FHS (n = 3260) and five independent external cohorts (n = 4021) showed that the baseline ERS was not associated with a change in BP over time or with incident HTN.

Conclusions

Our findings demonstrate that the ERS has potential clinical utility in assessing lifestyle factors related to cardiovascular risk, especially when self-reported behavioral data (e.g., alcohol consumption) are unreliable or unavailable.

Background

The P-wave duration (PWD) is an electrocardiographic measurement that represents cardiac conduction in the atria. Shortened or prolonged PWD is associated with atrial fibrillation (AF). We used exome-chip data to examine the associations between common and rare variants with PWD.

Methods

Fifteen studies comprising 64 440 individuals (56 943 European, 5681 African, 1186 Hispanic, 630 Asian) and ≈230 000 variants were used to examine associations with maximum PWD across the 12-lead ECG. Meta-analyses summarized association results for common variants; gene-based burden and sequence kernel association tests examined low-frequency variant-PWD associations. Additionally, we examined the associations between PWD loci and AF using previous AF genome-wide association studies.

Results

We identified 21 common and low-frequency genetic loci (14 novel) associated with maximum PWD, including several AF loci (TTN, CAND2, SCN10A, PITX2, CAV1, SYNPO2L, SOX5, TBX5, MYH6, RPL3L). The top variants at known sarcomere genes (TTN, MYH6) were associated with longer PWD and increased AF risk. However, top variants at other loci (eg, PITX2 and SCN10A) were associated with longer PWD but lower AF risk.

Conclusions

Our results highlight multiple novel genetic loci associated with PWD, and underscore the shared mechanisms of atrial conduction and AF. Prolonged PWD may be an endophenotype for several different genetic mechanisms of AF.