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Men and women differ substantially regarding height, weight, and body fat. Interestingly, previous work detecting genetic effects for waist-to-hip ratio, to assess body fat distribution, has found that many of these showed sex-differences. However, systematic searches for sex-differences in genetic effects have not yet been conducted. Therefore, we undertook a genome-wide search for sexually dimorphic genetic effects for anthropometric traits including 133,723 individuals in a large meta-analysis and followed promising variants in further 137,052 individuals, including a total of 94 studies. We identified seven loci with significant sex-difference including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were significant in women, but not in men. Of interest is that sex-difference was only observed for waist phenotypes, but not for height or body-mass-index. We found no evidence for sex-differences with opposite effect direction for men and women. The PPARG locus is of specific interest due to its link to diabetes genetics and therapy. Our findings demonstrate the importance of investigating sex differences, which may lead to a better understanding of disease mechanisms with a potential relevance to treatment options.
Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 22 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci, and results from rare variant exome sequencing in BD. Convergent lines of evidence supported the roles of SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, YWHAE, DPH1, GSDMB, MED24, THRA, EEF1A2, and KCNQ2 in BD. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance and transferability of BD polygenic risk scores across ancestrally diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI).
This thesis represents an original contribution to research in offering a comprehensive analysis of the work of Rudolf Bahro. The thesis combines a study of Bahro's work as a prominent opposition figure in the German Democratic Republic in the 1970s with an assessment of his career as an outspoken member of the West German Green Party in the 1980s. The core of the thesis is devoted to a thorough reappraisal of Bahro's major critique of 'actually existing socialism' in East Germany, Die Alternative - Zyr Kraik des real existierenden Sozialismus. Bahro's harsh critique of the SED is explored within the context of the GDR's historical development and Eastern European Marxist revisionism in general. A critical analysis of the extensive secondary literature which now surrounds this work is undertaken to discover how far existing interpretations offer an accurate assessment of Die Alternative. A further section compares for the first time the differing reception of Bahro's study in both East and West Germany. Bahro's earliest essays as an editor of the GDR journal Forum and his first critical work ... die nicht mit den Wolfen heulen are discussed as a key to establishing the particular nature of his opposition. Later chapters trace the development of Sahro's theories and discuss his contribution to the peace and ecology debates in West Germany in the 1980s. Bahro's efforts to achieve a synthesis of the interests of ecology and socialism are explored and his 'Fundamentalist' version of Green politics is discussed within the context of the Green Party's early development. The thesis concludes with an assessment of the increasingly radical utopianism permeating Bahro's writings and offers a critical examination of his attempts to infuse the ecology debate with a spiritual dimension, as detailed in Logik der Rettung, his chief work written in West Germany.