Combining genome-wide association studies highlight novel loci involved in human facial variation

Xiong, Zhenzhen; Gao, Xingjian; Chen, Yan; Feng, Zhanying; Pan, Siyu; Lu, Haojie; Uitterlinden, André G.; Nijsten, Tamar; Ikram, M. Arfan; Rivadeneira, Fernando; Ghanbari, Mohsen; Wang, Yong; Kayser, Manfred; Liu, Fan

doi:10.1038/s41467-022-35328-9

Cited by 11 publications

(18 citation statements)

References 49 publications

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“…Selecting clinically homogenous traits is the strategy most commonly used 4,8, 10,14–19 . In our previous large-scale analysis 8 , an heterogeneous set yielded the largest number of new association as compared to clinically homogenous sets.…”

Section: Discussionmentioning

confidence: 99%

Trait selection strategy in multi-trait GWAS: Boosting SNPs discoverability

Suzuki,

Ménager,

Brancotte

et al. 2023

Preprint

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Since the first Genome-Wide Association Studies (GWAS), thousands of variant-trait associations have been discovered. However, the sample size required to detect additional variants using standard univariate association screening is increasingly prohibitive. Multi-trait GWAS offers a relevant alternative: it can improve statistical power and lead to new insights about gene function and the joint genetic architecture of human phenotypes. Although many methodological hurdles of multi-trait testing have been discussed, the strategy to select trait, among overwhelming possibilities, has been overlooked. In this study, we conducted extensive multi-trait tests using JASS (Joint Analysis of Summary Statistics) and assessed which genetic features of the analysed sets were associated with an increased detection of variants as compared to univariate screening. Our analyses identified multiple factors associated with the gain in the association detection in multi-trait tests. Together, these factors of the analysed sets are predictive of the gain of the multi-trait test (Pearson's rho equal to 0.43 between the observed and predicted gain, P < 1.6 x 10-60). Applying an alternative multi-trait approach (MTAG, multi-trait analysis of GWAS), we found that in most scenarios but particularly those with larger numbers of traits, JASS outperformed MTAG. Finally, we benchmark several strategies to select set of traits including the prevalent strategy of selecting clinically similar traits, which systematically underperformed selecting clinically heterogenous traits or selecting sets that issued from our data-driven models. This work provides a unique picture of the determinant of multi-trait GWAS statistical power and outline practical strategies for multi-trait testing.

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Section: Discussionmentioning

confidence: 99%

Trait selection strategy in multi-trait GWAS: Boosting SNPs discoverability

Suzuki,

Ménager,

Brancotte

et al. 2023

Preprint

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show abstract

“…With advances in molecular biology technologies, data mining, and access to metadata, it is important to assess whether the past informed consent process and in particular associated risks are concomitant with these increased capabilities. In more recent years, genetic markers (single nucleotide polymorphisms (SNPs)) have been used to predict externally visible traits, such as eye color, hair color, skin pigmentation, and freckles, to support investigative leads [38][39][40][41][42][43].…”

Section: Enhanced Technical Capabilitiesmentioning

confidence: 99%

Revisiting informed consent in forensic genomics in light of current technologies and the times

Budowle

Sajantila

2023

Int J Legal Med

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Informed consent is based on basic ethical principles that should be considered when conducting biomedical and behavioral research involving human subjects. These principles—respect, beneficence, and justice—form the foundations of informed consent which in itself is grounded on three fundamental elements: information, comprehension, and voluntary participation. While informed consent has focused on human subjects and research, the practice has been adopted willingly in the forensic science arena primarily to acquire reference samples from family members to assist in identifying missing persons. With advances in molecular biology technologies, data mining, and access to metadata, it is important to assess whether the past informed consent process and in particular associated risks are concomitant with these increased capabilities. Given the state-of-the-art, areas in which informed consent may need to be modified and augmented are as follows: reference samples from family members in missing persons or unidentified human remains cases; targeted analysis of an individual(s) during forensic genetic genealogy cases to reduce an investigative burden; donors who provide their samples for validation studies (to include population studies and entry into databases that would be applied to forensic statistical calculations) to support implementation of procedures and operations of the forensic laboratory; family members that may contribute samples or obtain genetic information from a molecular autopsy; and use of medical and other acquired samples that could be informative for identification purposes. The informed consent process should cover (1) purpose for collection of samples; (2) process to analyze the samples (to include type of data); (3) benefits (to donor, target, family, community, etc. as applicable); (4) risks (to donor, target, family, community, etc. as applicable); (5) access to data/reports by the donor; (6) sample disposition; (7) removal of data process (i.e., expungement); (8) process to ask questions/assessment of comprehension; (9) follow-up processes; and (10) voluntary, signed, and dated consent. Issues surrounding these topics are discussed with an emphasis on addressing risk factors. Addressing informed consent will allow human subjects to make decisions voluntarily and with autonomy as well as secure the use of samples for intended use.

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“…We conducted the sex-mixed multivariate GWAS using C-GWAS 42 , which can utilize the shared genetic information of amygdala volumetric traits to improve genetic discovery. C-GWAS was performed based on the summary data for the volumes of the 20 symmetrical amygdala structures from the sex-mixed univariate EAS-GWASs, EUR-GWASs, and cross-ancestry GWAS meta-analyses, respectively.…”

Section: Genetic Associations In Sex-mixed Multivariate Gwassmentioning

confidence: 99%

“…Considering the correlation structure of amygdala volumetric traits (Supplementary Fig. 16), we further used C-GWAS (https://github.com/Fun-Gene/CGWAS) to combine the GWAS summary data of multiple correlated traits 42 to enhance the discovery of genetic variants associated with amygdala volumetric traits in EAS-GWASs, EUR-GWASs, and cross-ancestry GWAS meta-analysis. By virtue of complementarity of the iterative effect-based inversed covariance weighting and truncated Wald test, C-GWAS shows increased power in detecting multi-trait effects under diverse complex scenarios, with a particular focus on the SNPs with varying effects across GWASs of correlated traits 42 .…”

Section: Sex-mixed Multivariate Gwassmentioning

confidence: 99%

Cross-ancestry and sex-stratified genome-wide association analyses of amygdala and subnucleus volumes

Yu,

Ji,

Liu

et al. 2023

Preprint

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The amygdala is a small but critical multi-nucleus structure for emotion, cognition, and neuropsychiatric disorders. Although genetic associations with amygdala and subnucleus volumes have been investigated in sex-mixed European populations, cross-ancestry and sex-stratified analyses are still lacking. Here we conducted cross-ancestry and sex-stratified genome-wide association analyses for 21 amygdala volumetric traits in 6,923 Chinese and 48,634 European individuals. We identified 191 variant-trait associations (P < 2.38 × 10−9), including 47 new associations (12 new loci) in sex-mixed univariate analyses and seven additional new loci in sex-mixed and sex-stratified multivariate analyses. We identified 12 ancestry-specific and two sex-specific associations. The identified genetic variants include 16 fine-mapped causal variants and regulate amygdala and fetal brain gene expression. They are enriched for brain development and affect mood, cognition, and neuropsychiatric disorders. These results indicate that cross-ancestry and sex-stratified genetic association analyses may provide insight into the genetic architectures of amygdala and subnucleus volumes.

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Combining genome-wide association studies highlight novel loci involved in human facial variation

Cited by 11 publications

References 49 publications

Trait selection strategy in multi-trait GWAS: Boosting SNPs discoverability

Trait selection strategy in multi-trait GWAS: Boosting SNPs discoverability

Revisiting informed consent in forensic genomics in light of current technologies and the times

Cross-ancestry and sex-stratified genome-wide association analyses of amygdala and subnucleus volumes

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