Polygenic risk scores (PRS) have attenuated cross-population predictive performance. As existing genomewide association studies (GWAS) were predominantly conducted in individuals of European descent, the limited transferability of PRS reduces its clinical value in non-European populations and may exacerbate healthcare disparities. Recent efforts to level ancestry imbalance in genomic research have expanded the scale of non-European GWAS, although they remain under-powered. Here we present a novel PRS construction method, PRS-CSx, which improves cross-population polygenic prediction by integrating GWAS summary statistics from multiple populations. PRS-CSx couples genetic effects across populations via a shared continuous shrinkage prior, enabling more accurate effect size estimation by sharing information between summary statistics and leveraging linkage disequilibrium (LD) diversity across discovery samples, while inheriting computational efficiency and robustness from PRS-CS. We show that PRS-CSx outperforms alternative methods across traits with a wide range of genetic architectures and cross-population genetic correlations in simulations, and substantially improves the prediction of quantitative traits and schizophrenia risk in non-European populations.

The MICOS complex (mitochondrial contact site and cristae organizing system) is essential for mitochondrial inner membrane organization and mitochondrial membrane contacts, however, the molecular regulation of MICOS assembly and the physiological functions of MICOS in mammals remain obscure. Here, we report that Mic60/Mitofilin has a critical role in the MICOS assembly, which determines the mitochondrial morphology and mitochondrial DNA (mtDNA) organization. The downregulation of Mic60/Mitofilin or Mic19/CHCHD3 results in instability of other MICOS components, disassembly of MICOS complex and disorganized mitochondrial cristae. We show that there exists direct interaction between Mic60/Mitofilin and Mic19/CHCHD3, which is crucial for their stabilization in mammals. Importantly, we identified that the mitochondrial i-AAA protease Yme1L regulates Mic60/Mitofilin homeostasis. Impaired MICOS assembly causes the formation of 'giant mitochondria' because of dysregulated mitochondrial fusion and fission. Also, mtDNA nucleoids are disorganized and clustered in these giant mitochondria in which mtDNA transcription is attenuated because of remarkable downregulation of some key mtDNA nucleoid-associated proteins.Together, these findings demonstrate that Mic60/Mitofilin homeostasis regulated by Yme1L is central to the MICOS assembly, which is required for maintenance of mitochondrial morphology and organization of mtDNA nucleoids. Mitochondria have a key role in oxidative phosphorylation and related cellular metabolism, in energy conversion, in programmed cell death, in cell growth and in diseases. Mitochondrial outer and inner membranes strongly differ in architecture and functions. The mitochondrial outer membrane forms a barrier to cytosol, and contains channels and the translocases of outer membrane, which is the main protein entry gate of mitochondria. 1,2 In contrast, the mitochondrial inner membrane consists of two morphologically distinct regions: the inner boundary membrane is in close proximity to the outer membrane and the cristae membranes that are large tubular invaginations. [3][4][5][6][7][8] The mitochondrial inner boundary and cristae membrane are physically separated by cristae junctions, which are narrow tubular or slot-like structure. 4,9 The mitochondrial cristae are arranged in regular arrays and are the main sites of ATP production in the mitochondria, but the molecules that are associated with the maintenance of cristae architecture still remain elusive. Recently, several groups identified a large protein complex, MICOS complex (mitochondrial contact site and cristae organizing system; previously named MINOS, MitOS, Mitofilin or Fcj1 complex ), that has a crucial role in the formation of cristae junctions, contact sites to the outer membrane, and the organization of inner membrane. [10][11][12][13][14] In yeast, MICOS consists of at least six subunits: Mic60 (Fcj1), Mic10 (Mio10/Mcs10/Mos1), Mic19 (Aim13/Mcs19), Mic26 (Mio27/Mcs29/Mos2), Mic12 (Aim5/ Msc12) and Mic27 (Aim37/Mcs27). In mammals, five s...

Polygenic risk scores (PRS) have attenuated cross-population predictive performance. As existing genome-wide association studies (GWAS) were predominantly conducted in individuals of European descent, the limited transferability of PRS reduces its clinical value in non-European populations and may exacerbate healthcare disparities. Recent efforts to level ancestry imbalance in genomic research have expanded the scale of non-European GWAS, although they remain under-powered. Here we present a novel PRS construction method, PRS-CSx, which improves cross-population polygenic prediction by integrating GWAS summary statistics from multiple populations. PRS-CSx couples genetic effects across populations via a shared continuous shrinkage prior, enabling more accurate effect size estimation by sharing information between summary statistics and leveraging linkage disequilibrium (LD) diversity across discovery samples, while inheriting computational efficiency and robustness from PRS-CS. We show that PRS-CSx outperforms alternative methods across traits with a wide range of genetic architectures and cross-population genetic correlations in simulations, and substantially improves the prediction of quantitative traits and schizophrenia risk in non-European populations.