Search

Cattle temperament is an interesting trait due to its correlation with production efficiency, labor safety, and animal welfare. To date, however, its genetic basis is not clearly understood. Here, we performed a genome-wide association study for a series of temperament traits in cattle, assessed with via open field and novel object tests, using autosomal single nucleotide polymorphisms (SNPs) derived from the whole-genome sequence. We identified 37 and 29 genome-wide significant loci in the open field and novel object tests, respectively. Gene set analysis revealed the most significant pathway was the neuroactive ligand-receptor interaction pathway, which may be essential for emotional control in cattle. Analysis of the expression levels of 18 tissue-specific genes based on transcriptomic data showed enrichment in the brain, with some candidate genes involved in psychiatric and neurodegenerative diseases in humans. Based on principal component analysis, the first principal component explained the largest variance in the open field and novel object test data, and the most significant loci were assigned to牛性情是一个非常有意思的性状，它与生产效率、役用安全、动物福利等紧密相关，但其遗传机制尚不清楚。该研究通过旷场测试及新物体测试分别获得了15和14个与性情相关的性状数据，结合30头婆罗门牛及128头云岭牛的常染色体基因组序列单核苷酸多态性(SNPs)进行全基因组关联分析（GWAS）。结果显示在旷场测试和新物体测试中分别鉴定出37 和29个显著位点。基因注释发现多个旷场测试性状的显著位点位于参与突触抑制和恐惧消退神经元受体基因

Wild yak (Bos mutus) is a vulnerable bovine species on the Qinghai-Tibetan Plateau. So far, most studies on the molecular genetic diversity of wild yak have focused on autosomal and mtDNA variations based on the small number of samples. In this study, we analyzed 84 D-loop and 24 whole mitogenome sequences of wild yak to further comprehensively explore its maternal genetic diversity and lineage composition. Meanwhile, using six yak Y-specific polymorphic markers (i.e., SRY4, USP9Y, UTY19, AMELY3, OFD1Y10 and INRA189), we assessed the paternal genetic diversity and lineage composition based on eight wild yak. Our results showed that wild yak exhibited abundant maternal genetic diversity with haplotype diversities of 0.9621 ± 0.0078 and 0.9928 ± 0.0144 in the D-loop and whole mitogenome sequences, respectively. Maternal phylogenetic analysis of wild yak uncovered three defined lineages (mt-I, mt-II and mt-III). Similarly, profuse paternal genetic diversity was observed in wild yak with Y-haplotype diversity at 0.8214 ± 0.1007. Two Y-haplogroups (Y1 and Y2) and four Y-haplotypes (yH1-yH4) were identified in paternal phylogenetic analysis, indicating wild yak to be of two paternal lineages. The present study of genetic diversity and lineage composition of wild yak would provide useful information for the genetic resource conservation and utilization of this vulnerable wild species.

Copy number variation (CNV) is the most prevalent type of genetic structural variation that has been recognized as an important source of phenotypic variation in humans, animals and plants. However, the mechanisms underlying the evolution of CNVs and their function in natural or artificial selection remain unknown. Here, we generated CNV region (CNVR) datasets which were diverged or shared among cattle, goat, and sheep, including 886 individuals from 171 diverse populations. Using 9 environmental factors for genome-wide association study (GWAS), we identified a series of candidate CNVRs, including genes relating to immunity, tick resistance, multi-drug resistance, and muscle development. The number of CNVRs shared between species is significantly higher than expected (P

The swamp buffalo (Bubalus carabanensis) is mainly bred for meat, transport and rice cultivation in China and Southeast Asian countries. In the current study, we investigated the genetic diversity, maternal origin and phylogenetic relationship of swamp buffalo by analyzing 1,786 mitochondrial cytochrome b (cytb) sequences from China, Vietnam, Laos, Thailand, India and Bangladesh. Our results indicated that the swamp buffalo can be divided into two major lineages (SA and SB with the sublineages) and three rare lineages (SC, SD and SE), which showed strong geographic differentiation. The SA1 lineage represented a major domestication event, which involved population expansion. Regions III and V showed higher haplotype diversity than the other regions, indicating that the regions of Southwest China and IndoChina are potential domestication centers for the swamp buffalo. In addition, the swamp buffalo showed a closer phylogenetic relationship to tamaraw. In conclusion, our findings revealed a high level of genetic diversity and the phylogenetic pattern of the swamp buffalo.

Marbling score (MS), is an economically important trait in cattle. Previous results showed that a SNP (c.*188G > A) of akirin 2 (AKIRIN2) gene was associated with MS in Japanese Black cattle and Ko...

European taurine and East Asian taurine are two main clades in Bos taurus, but their genomic differences are not clearly elucidated. Here, we sequenced 16 Mongolian cattle genomes and compared them to the 92 genomes of 10 representative breeds worldwide. We found the highest LD level in Mishima cattle and the fastest LD decay in European taurine. Phylogenetic analysis revealed that Mongolian, Hanwoo and Mishima cattle were clustered into East Asian taurine. From selective sweep, gene annotation, functional enrichment and differential expression analysis, we identified selective signals including genes and/or pathways related to rapid growth and large body size in European taurine, and superior meat quality in East Asian taurine. Our findings will help us understand the evolutionary history and formation process of the breeds and provide theoretical materials regarding the genetic mechanism underlying breed characteristics and molecular breeding programmes of the taurine clades in the future.

Yunling cattle, a three-breed cross consisting of 1/2 Brahman cattle, 1/4 Murray Grey cattle and 1/4 Yunnan Yellow cattle, has advantage of rapid growth, good meat quality, enhanced tolerance towards a hot and humid climate, tick resistance and crude feed forbearance. Here, we investigated the genetic diversity, global and local ancestry proportions by sequencing the genomes of 131 Yungling cattle and 31 Brahman cattle (for control). Furthermore, we used 35 published genomes of ancestry breeds (including Angus cattle [ancestry of Murray Grey], Wannan cattle [ancestry of Yunnan Yellow cattle: Wenshan and Dianzhong], Wenshan and Dianzhong cattle) to characterize the formation process of Yunling cattle. The highest nucleotide diversity was found in the Wannan cattle, followed by Wenshan, Dianzhong, Brahman, Yunling and Angus cattle. The results of LD decay in each breed was largely consistent with the results of nucleotide diversity, except for the faster decay in Angus cattle out of a smaller effective population size and a strong bottleneck during the breed formation. The population-structure analysis revealed that the cross-breed Yunling cattle harboured the ancestry with Angus (0.44), Brahman (0.48) and Wannan cattle (0.08). Subsequently, we used RFmix to infer local ancestry in Yunling cattle and then performed chi-squared test to obtain the segments whose proportions of a certain ancestry were excessive compared with the whole-genome level, leading to 391 Angus, 49 Brahman and 2,312 Wannan segments. Gene annotation and KEGG enrichment analysis revealed that the excessive Angus, Brahman and Wannan segments might contribute to the rapid growth, immune resistance and indigenous adaptation, respectively, in Yunling cattle. Our results help understand ancestry components and formation process in Yunling cattle and will provide an opportunity for selective breeding by molecular approaches in future.

Heat stress affects the animal production and causes serious economic losses to the husbandry. Tectonin beta-propeller repeat containing 2 (

Yunling cattle (YL) is a recently developed beef breed harboring a quarter of Yunnan ancestral cattle genome, spanning over past 30 years. Compared with Diqing cattle (DQ), a Yunnan native cattle breed, YL presents various advantages, including rapid growth and exquisite meat quality. However, the molecular mechanisms underlying these phenotypic differences are not clearly understood. To further identify the candidate genes responsible for the quality of the meat in the muscle, longissimus dorsi (LD) muscle was used for RNA-Seq analysis. A total of 508 differentially expressed genes (DEGs) were identified in YL (adjusted

Stature is an important quantitative trait for cattle performance, which influences herd productivity. Previous studies have reported that an SNP (AC_000171.1:g.25015640G>T, rs109815800) in Pleomorphic adenoma gene 1 (PLAG1) on chromosome 14 (CHR14) is associated with bovine stature. To validate whether rs109815800 is associated with the body height of Chinese cattle, we carried out an association analysis using 558 adult cattle samples from seven populations. Then, 1038 samples from 38 Chinese cattle breeds were used to show the geographical distribution of this variant in China. The results showed that the Q allele (G allele) increased the height of cattle. Furthermore, the frequencies of Q allele in Chinese native breeds tend to decrease from northern China to southern China, and the frequency of Q allele in two Chinese beef cattle breeds is much higher than that in another 36 Chinese local cattle breeds. Our data suggest that the prevalence of the Q allele is correlated with latitude in China.

White yak is a unique economic livestock animal on the Qilian Mountains of Qinghai-Tibet Plateau (QTP). Here, 369 mitochondrial D-loop sequences from three Chinese white yak breeds/populations (Tianzhu, Menyuan and Huzhu) were comprehensively analyzed to indicate their maternal genetic diversity, differentiation and phylogenetic relationship. Our results showed that the haplotype diversity (Hd) was found to be highest in Tianzhu white yak (Hd ± SD = 0.9501 ± 0.0058), while the lowest was recorded in Huzhu white yak (Hd ± SD = 0.7178 ± 0.0474). Totally, the haplotype and nucleotide diversities of white yak were 0.9407 ± 0.0069 and 0.0187 ± 0.0094, respectively, indicating an abundant maternal genetic diversity in white yak. Estimates of FST (Fixation Index) values showed a high genetic differentiation between Tianzhu and Menyuan populations (FST = 0.2928, p 0.05) was observed. Cluster analysis based on FST values among populations indicated that the genetic relationship between Menyuan and Huzhu white yak was closer, but they had a far genetic relationship with Tianzhu white yak. Maternal phylogenetic analysis revealed that white yak represented two maternal lineages (I and II), suggesting two maternal origins. In addition, it is notable that taurine mtDNA haplotypes were detected in Tianzhu and Huzhu white yak populations, indicating taurine genetic introgression to some extent. Our study would provide useful information for the conservation and utilization of white yak.

Heat stress affects the animal production and causes serious economic losses to the husbandry. Tectonin beta-propeller repeat containing 2 (TECPR2) gene plays an important role in autophagy which may affect the temperature sensation in animals. A missense mutation (XM_024981840.1:c.3989 G > A p.Arg1330His) of the transcripts X4 in the bovine TECPR2 gene was identified. In this study, the c.3989 G > A variant in TECPR2 gene was genotyped in a total of 25 cattle breeds (520 individuals). Our results indicated that the frequency of A allele showed a decreasing pattern from southern cattle to northern cattle, while the frequency of G allele showed the opposite pattern, which was consistent with the climate distribution of China. Compared with the GG genotype, southern cattle carried more the AA and AG genotypes. Furthermore, the association results carried out that the frequencies of genotypes (GG, AG, AA) and the value of climate parameters (mean annual temperature (T), relative humidity (RH) and temperature humidity index (THI) were significantly correlated (p A variant of TECPR2 gene was associated with the heat tolerance trait in Chinese cattle and the locus may be considered as a molecular marker for Chinese cattle breeding.

BackgroundEar size is a classical model for hot climate adaptation following evolution, however, the genetic basis of the traits associated with the ear size remains to be elucidated.ResultsIn the current study, we performed GWAS on 158 cattle individuals to to explain the genetic mechanism of ear size. The results suggested significant association of IBSP locus with ear size. A missense mutation (Threonine-250→Isoleucine) on the seventh exon of IBSP was observed, which occurred at a quite conserved site and changed the three-dimensional (3D) structure simulations. In addition to GWAS, 14 cattle breeds were screened for the selection signals associating with the ear size using Fst and SweepD. The selective sweep analysis also suggested that IBSP was under positive selection amongst 4 breeds with relatively large ear size. The allele distribution of this mutation was validated among 394 samples from 21 worldwide cattle breeds, which strongly implied the origin of the A allele mutation to be from the Bos taurus.ConclusionsThese findings not only have important theoretical significance for the exploration of major genes associated with the ear size but also provide important molecular markers for the identification of cattle germplasm resources.

BackgroundCattle temperament is one of the most interesting traits owing to its correlation to productive efficiency, labor safety and animal welfare, but its genetic basis is not clearly understood.ResultsHere, we performed genome-wide association studies for a series of temperament traits, assessed in an open field and novel object test, using autosomal SNPs derived from the whole-genome sequence. We identified 37 and 29 genome-wide significant loci in an open field and novel object test, respectively. Gene set analysis implicated the neuroactive ligand-receptor interaction pathway. Analysis in tissue specific expressions showed enrichment in the brain. While some candidate genes were involved in psychiatric and neurodegenerative diseases in humans. The first principal component explained the largest variance in the data of open field and novel object test, and the most significant loci were assigned to SORCS3 and SESTD1, respectively.ConclusionsOur findings will facilitate cattle breeding for sound temperament by pyramiding favorable alleles to further improve the cattle production in the future.

The Longlin goat is one of the most valuable livestock species in Guangxi Autonomous Region of China, but its genomic diversity and selective signals are not clearly elucidated. Here we compared 20 genomes of Longlin goat to 66 genomes of other seven goat breeds worldwide to analyze patterns of Longlin goat genetic variation. We found the lowest linkage disequilibrium at the large distances between SNPs associated with the highest effective population size in the recent generations ago in Longlin goat. The eight goat breeds could be divided into Euro-African and East Asian goat population. Interestingly, like East Asian taurine, the same two migration phases might have occurred in the history of East Asian goat. More importantly, we identified selective signals implicated in immune resistance to disease, especially for skin disease, in Longlin goat. Our findings will not only help understand the evolutionary history and breed characteristic but can provide valuable resources for conservation of germplasm resources and implementation of crossbreeding programs.

Marbling score (MS), is an economically important trait in cattle. Previous results showed that a SNP (

Copy number variation (CNV) is the most prevalent type of genetic structural variation that has been recognized as an important source of phenotypic variation in humans, animals and plants. However, the mechanisms underlying the evolution of CNVs and their function in natural or artificial selection remain unknown. Here, we generated CNV region (CNVR) datasets which were diverged or shared among cattle, goat, and sheep, including 886 individuals from 171 diverse populations. Using 9 environmental factors for genome-wide association study (GWAS), we identified a series of candidate CNVRs, including genes relating to immunity, tick resistance, multi-drug resistance, and muscle development. The number of CNVRs shared between species is significantly higher than expected (P0.00001), and these CNVRs may be more persist than the single nucleotide polymorphisms (SNPs) shared between species. We also identified genomic regions under long-term balancing selection and uncovered the potential diversity of the selected CNVRs close to the important functional genes. This study provides the evidence that balancing selection might be more common in mammals than previously considered, and might play an important role in the daily activities of these ruminant species.

Copy number variations (CNVs) are important source of genetic variation, which can affect diverse economic traits through a variety of mechanisms. In addition, genome scan can identify many quantitative trait loci (QTLs) for the economic traits, while genome-wide association studies (GWAS) can localize genetic variants associated with the phenotypic variations. Here, we developed a method called GWAScore which collected GWAS summary data to identify potential candidates, and integrated CNVs into QTLs and high confidence GWAScore regions to detect crucial CNV markers for sheep growth traits. We got 197 candidate genes which were overlapping with the candidate CNVs. Some crucial genes (MYLK3, TTC29, HERC6, ABCG2, RUNX1, etc.) showed significantly elevated GWAScore peaks than other candidate genes. In this study, we developed the GWAScore method to excavate the potential value of candidate genes as markers for the sheep molecular breeding.

Additional file 2:Supplementary Figure 1. Geographic distribution of the four Chinese sheep breeds. (We state that the map and CKA images depicted in Supplementary Figure 1 were our own. TAN, BYK and OLA images were from this paper [12] and we obtained written permission from the copyright holders to use and adapt these images depicted in Supplementary Figure 1.)

Background Chaka sheep, named after Chaka Salt Lake, are adapted to a harsh, highly saline environment. They are known for their high-grade meat quality and are a valuable genetic resource in China. Furthermore, the Chaka sheep breed has been designated a geographical symbol of agricultural products by the Chinese Ministry of Agriculture. Results The genomes of 10 Chaka sheep were sequenced using next-generation sequencing, and compared to that of additional Chinese sheep breeds (Mongolian: Bayinbuluke and Tan; Tibetan: Oula sheep) to explore its population structure, genetic diversity and positive selection signatures. Principle component analysis and a neighbor-joining tree indicated that Chaka sheep significantly diverged from Bayinbuluke, Tan, and Oula sheep. Moreover, they were found to have descended from unique ancestors (K = 2 and K = 3) according to the structure analysis. The Chaka sheep genome demonstrated comparable genetic diversity from the other three breeds, as indicated by observed heterozygosity (Ho), expected heterozygosity (He), runs of homozygosity (ROH), linkage disequilibrium (LD) decay. The enrichment analysis revealed that in contrast to Mongolian or Tibetan lineage groups, the genes annotated by specific missense mutations of Chaka sheep were enriched with muscle structure development (GO:0061061) factors including insulin-like growth factor 1 (IGF1), growth differentiation factor 3 (GDF3), histone deacetylase 9 (HDAC9), transforming growth factor beta receptor 2 (TGFBR2), and calpain 3 (CAPN3), among others. A genome-wide scan using Fst and XP-CLR revealed a list of muscle-related genes, including neurofibromin 1 (NF1) and myomesin 1 (MYOM1), under potential selection in Chaka sheep compared with other breeds. Conclusions The comprehensive genome-wide characterization provided the fundamental footprints for breeding and management of the Chaka sheep and confirmed that they harbor unique genetic resources.

Based on the previous GWAS research related to bovine heat tolerance trait, this study aimed to explore the effect of myosin-1a (MYO1A) gene on bovine heat tolerance trait, and find the molecular markers related to the heat tolerance of Chinese cattle. In our study, four novel candidate SNPs highly conserved in B. indicus breeds but barely existed in B. taurus were identified in MYO1A gene according to Bovine Genome Variation Database and Selective Signatures (BGVD). PCR and DNA sequencing were used to genotype 1072 individuals including 34 Chinese indigenous cattle breeds as well as Angus and Indian zebu. Two synonymous mutations (rs208210464 and rs110123931), one missense mutation (rs209999142, Phe172Ser), and one intron mutation (rs135771836) were detected. The frequencies of mutant alleles of the four SNPs gradually increased from northern groups to southern groups of Chinese cattle, which was consistent with the distribution of various climatic conditions of China. Additionally, four SNPs were significantly associated with four climatic conditions including annual mean temperature (T), relative humidity (H), temperature-humidity index (THI), and average annual sunshine hours (100-cloudiness) (SR). Among these, rs209999142 and Hap 1/1 had better performance than others. Our results suggested that rs209999142 was associated with heat-tolerance trait and rs208210464, rs110123931, and rs135771836 showed high phenotypic effect on heat-tolerance trait because of the strong linkage with rs209999142. These SNPs could be used as candidates for marker-assisted selection (MAS) in cattle breeding.

Simple Summary Chinese indigenous cattle were clustered into two groups of southern and northern breeds. The populations distributed in the hot south are mainly dominated by Bos indicus, and the populations distributed in the cold north are mainly dominated by Bos taurus. Myosin-1a (MYO1A) gene is a candidate gene related to pigmentation, which may be closely related to the heat tolerance traits of cattle. Therefore, our study aimed to explore the relationship between MYO1A gene and heat tolerance in Chinese indigenous cattle. Abstract Based on the previous GWAS research related to bovine heat tolerance trait, this study aimed to explore the effect of myosin-1a (MYO1A) gene on bovine heat tolerance trait, and find the molecular markers related to the heat tolerance of Chinese cattle. In our study, four novel candidate SNPs highly conserved in B. indicus breeds but barely existed in B. taurus were identified in MYO1A gene according to Bovine Genome Variation Database and Selective Signatures (BGVD). PCR and DNA sequencing were used to genotype 1072 individuals including 34 Chinese indigenous cattle breeds as well as Angus and Indian zebu. Two synonymous mutations (rs208210464 and rs110123931), one missense mutation (rs209999142; Phe172Ser), and one intron mutation (rs135771836) were detected. The frequencies of mutant alleles of the four SNPs gradually increased from northern groups to southern groups of Chinese cattle, which was consistent with the distribution of various climatic conditions of China. Additionally, four SNPs were significantly associated with four climatic conditions including annual mean temperature (T), relative humidity (H), temperature-humidity index (THI), and average annual sunshine hours (100-cloudiness) (SR). Among these, rs209999142 and Hap 1/1 had better performance than others. Our results suggested that rs209999142 was associated with heat-tolerance trait and rs208210464, rs110123931, and rs135771836 showed high phenotypic effect on heat-tolerance trait because of the strong linkage with rs209999142. These SNPs could be used as candidates for marker-assisted selection (MAS) in cattle breeding.

Lower flight reaction is closely related to higher production in cattle, but the genetic basis of lower flight reaction is not clearly understood. Here, we sampled a total of 45 Brahman cattles and 166 Yunling cattles with flight distance (FD), and 73 Brahman cattles and 288 Yunling cattles with crush score (CS) and flight speed (FS), whereas there were 45 Brahman cattles and 161 Yunling cattles with all three traits. The FD, CS and FS in Brahman cattle were significantly lower than those in Yunling cattle. The flight reaction traits had negative correlation with conformational traits (e.g., body weight, withers height and body length). Based on SNPs derived from a subset of 162 whole genomes (25 Brahman genomes and 100 Yunling genomes with FD, 30 Brahman and 131 Yunling genomes with CS and FS), genome-wide association study with mixed linear model was performed to test potential associations between flight reaction traits and genomic variants. We identified five, two and two genomic loci suggestively associated with FD, CS and FS, respectively. Five out of five candidate genes for FD (LOC789753, LRP6, CTIF, SLC9A9 and ZEB1) were reported to be related to Alzheimer's disease representing cognitive impairment in human, which was consistent with the finding that cognitive-behavioural intervention decreased the FD of cows to human. In CS, a very strong association locus was assigned to CDH8, a cadherin involved in synaptic adhesion, axon outgrowth and guidance, whose deletion was associated with autism spectrum disorder. In FS, a very strong association locus was assigned to GABRG2, a gamma-aminobutyric acid (a major inhibitory neurotransmitter in brain) receptor, whose polymorphisms were associated with suicidal behaviour in schizophrenia patients. Our findings will provide targets for molecular-marker selection and genetic manipulation of cattle improvement to meeting the growing demand for lower flight reaction to human.

Simple Summary Whole-genome resequencing is an important tool to reveal the in-depth genomic characteristics of a genome. Adaptability traits are key to the survival of the south Chinese zebu cattle. However, the potential genetic information behind these remarkable traits still remains uncertain and needs to be addressed. In the current study, we utilized a total of 15 local south Chinese cattle samples (Leiqiong (LQ), Wannan (WN), Wenshan (WS)) from one of our previous studies mapped to the old reference genome (Btau_5.0.1) and remapped them to the latest reference genome (ARS-UCD1.2) to explore potential single nucleotide polymorphisms (SNPs) and insertions-deletions (InDels) responsible for some important immune related traits. The present study emphasizes and illustrates the genetic diversity, extending our previous study. The InDel annotation show that WS cattle had more enriched genes associated with immune functions than the other two breeds. Our findings provide valuable resources for further investigation of the functions of SNP- and InDels-related genes and help to determine the molecular basis of adaptive mutations in Chinese zebu cattle. Abstract We report genome characterization of three native Chinese cattle breeds discovering ~34.3 M SNPs and ~3.8 M InDels using whole genome resequencing. On average, 10.4 M SNPs were shared amongst the three cattle breeds, whereas, 3.0 M, 4.9 M and 5.8 M were specific to LQ, WN and WS breeds, respectively. Gene ontology (GO)analysis revealed four immune response-related GO terms were over represented in all samples, while two immune signaling pathways were significantly over-represented in WS cattle. Altogether, we found immune related genes (PGLYRP2, ROMO1, FYB2, CD46, TSC1) in the three cattle breeds. Our study provides insights into the genetic basis of Chinese indicine adaptation to the tropic and subtropical environment, and provides a valuable resource for further investigations of genetic characteristics of the three breeds.

Ketosis (KET) is one common metabolic disorder that occurs mainly in early lactation and affects the dairy industry with significant economic losses. Cows with ketosis have lower milk yield and reproductive performance and greater risk of other periparturient diseases. As a metabolic disease, the pathogenesis of KET is multifactorial. To better understand the genetic background of KET, a genome-wide association study was performed using the Illumina BovineSNP50 BeadChip. Single-step genomic BLUP methodology was used to incorporate genomic data into a threshold-liability model. Results of the GWAS are reported as the proportion of variance explained by 20-SNP windows. Six genomic regions on Bos taurus autosomes 10, 13, 14 and 25 showed association with KET. Most interestingly, several candidate genes, including previously reported genes (BMP4, HNF4A and APOBR) and newly identified genes (SOCS4, GCH1, ATG14, RGS6, CYP7A1 and MAPK3), are involved in insulin metabolism or lipid metabolism, implicating the contribution of energy-metabolism-associated genes to the genetic basis of KET. Our results provide new information about the underlying biology and molecular mechanisms associated with KET. Future studies that combine genomic variation analysis and functional gene information may help elucidate the biology of KET.