Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10-5) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10-5). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10-10, odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression

The interplay of family history of depression and early trauma: associations with lifetime and current depression in the German national cohort (NAKO)

INTRODUCTION: Family history of depression and childhood maltreatment are established risk factors for depression. However, how these factors are interrelated and jointly influence depression risk is not well understood. The present study investigated (i) if childhood maltreatment is associated with a family history of depression (ii) if family history and childhood maltreatment are associated with increased lifetime and current depression, and whether both factors interact beyond their main effects, and (iii) if family history affects lifetime and current depression via childhood maltreatment. METHODS: Analyses were based on a subgroup of the first 100,000 participants of the German National Cohort (NAKO), with complete information (58,703 participants, mean age = 51.2 years, 53% female). Parental family history of depression was assessed via self-report, childhood maltreatment with the Childhood Trauma Screener (CTS), lifetime depression with self-reported physician's diagnosis and the Mini-International Neuropsychiatric Interview (MINI), and current depressive symptoms with the depression scale of the Patient Health Questionnaire (PHQ-9). Generalized linear models were used to test main and interaction effects. Mediation was tested using causal mediation analyses. RESULTS: Higher frequencies of the childhood maltreatment measures were found in subjects reporting a positive family history of depression. Family history and childhood maltreatment were independently associated with increased depression. No statistical interactions of family history and childhood maltreatment were found for the lifetime depression measures. For current depressive symptoms (PHQ-9 sum score), an interaction was found, with stronger associations of childhood maltreatment and depression in subjects with a positive family history. Childhood maltreatment was estimated to mediate 7%–12% of the effect of family history on depression, with higher mediated proportions in subjects whose parents had a depression onset below 40 years. Abuse showed stronger associations with family history and depression, and higher mediated proportions of family history effects on depression than neglect. DISCUSSION: The present study confirms the association of childhood maltreatment and family history with depression in a large population-based cohort. While analyses provide little evidence for the joint effects of both risk factors on depression beyond their individual effects, results are consistent with family history affecting depression via childhood maltreatment to a small extent

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Association Between Chromosome 9p21 Variants and the Ankle-Brachial Index Identified by a Meta-Analysis of 21 Genome-Wide Association Studies

Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based cohorts

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways

The interplay of family history of depression and early trauma: associations with lifetime and current depression in the German national cohort (NAKO)

IntroductionFamily history of depression and childhood maltreatment are established risk factors for depression. However, how these factors are interrelated and jointly influence depression risk is not well understood. The present study investigated (i) if childhood maltreatment is associated with a family history of depression (ii) if family history and childhood maltreatment are associated with increased lifetime and current depression, and whether both factors interact beyond their main effects, and (iii) if family history affects lifetime and current depression via childhood maltreatment.MethodsAnalyses were based on a subgroup of the first 100,000 participants of the German National Cohort (NAKO), with complete information (58,703 participants, mean age = 51.2 years, 53% female). Parental family history of depression was assessed via self-report, childhood maltreatment with the Childhood Trauma Screener (CTS), lifetime depression with self-reported physician's diagnosis and the Mini-International Neuropsychiatric Interview (MINI), and current depressive symptoms with the depression scale of the Patient Health Questionnaire (PHQ-9). Generalized linear models were used to test main and interaction effects. Mediation was tested using causal mediation analyses.ResultsHigher frequencies of the childhood maltreatment measures were found in subjects reporting a positive family history of depression. Family history and childhood maltreatment were independently associated with increased depression. No statistical interactions of family history and childhood maltreatment were found for the lifetime depression measures. For current depressive symptoms (PHQ-9 sum score), an interaction was found, with stronger associations of childhood maltreatment and depression in subjects with a positive family history. Childhood maltreatment was estimated to mediate 7%–12% of the effect of family history on depression, with higher mediated proportions in subjects whose parents had a depression onset below 40 years. Abuse showed stronger associations with family history and depression, and higher mediated proportions of family history effects on depression than neglect.DiscussionThe present study confirms the association of childhood maltreatment and family history with depression in a large population-based cohort. While analyses provide little evidence for the joint effects of both risk factors on depression beyond their individual effects, results are consistent with family history affecting depression via childhood maltreatment to a small extent

Abdominal Aortic Aneurysm Is Associated with a Variant in Low-Density Lipoprotein Receptor-Related Protein 1

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10−5) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10−5). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10−10, odds ratio 1.15 [1.10–1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04–1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways