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International Journal of Genomics logoLink to International Journal of Genomics
. 2023 Jul 27;2023:8497453. doi: 10.1155/2023/8497453

Genomic Regions and Candidate Genes Associated with Milk Production Traits in Holstein and Its Crossbred Cattle: A Review

R Bekele 1,2,✉, M Taye 1, G Abebe 1, S Meseret 3
PMCID: PMC10400298  PMID: 37547753

Abstract

Genome-wide association studies (GWAS) are a powerful tool for identifying genomic regions and causative genes associated with economically important traits in dairy cattle, particularly complex traits, such as milk production. This is possible due to advances in next-generation sequencing technology. This review summarized information on identified candidate genes and genomic regions associated with milk production traits in Holstein and its crossbreds from various regions of the world. Milk production traits are important in dairy cattle breeding programs because of their direct economic impact on the industry and their close relationship with nutritional requirements. GWAS has been used in a large number of studies to identify genomic regions and candidate genes associated with milk production traits in dairy cattle. Many genomic regions and candidate genes have already been identified in Holstein and its crossbreds. Genes and single nucleotide polymorphisms (SNPs) that significantly affect milk yield (MY) were found in all autosomal chromosomes except chromosomes 27 and 29. Half of the reported SNPs associated with fat yield and fat percentage were found on chromosome 14. However, a large number of significant SNPs for protein yield (PY) and protein percentage were found on chromosomes 1, 5, and 20. Approximately 155 SNPs with significant influence on multiple milk production traits have been identified. Several promising candidate genes, including diacylglycerol O-acyltransferase 1, plectin, Rho GTPase activating protein 39, protein phosphatase 1 regulatory subunit 16A, and sphingomyelin phosphodiesterase 5 were found to have pleiotropic effects on all five milk production traits. Thus, to improve milk production traits it is of practical relevance to focus on significant SNPs and pleiotropic genes frequently found to affect multiple milk production traits.

1. Introduction

Milk is a highly nutritious and valuable human food consumed by millions of people every day in a variety of flavors and products. Milk production traits, such as milk, fat, and protein yields (PYs), and fat and protein percentages (PPs), are the essential economic traits that are used to evaluate milk quantity and quality and play a major role in dairy development [1]. Milk traits are influenced by multiple genes, and therefore genomic evaluations have the potential to rapidly increase the rate of genetic improvement for these traits in dairy [2]. Understanding genetic variation in dairy cattle is crucial to associating genomic regions with milk yield (MY) and composition traits. The sequencing of the bovine genome in 2004 sparked a worldwide effort to improve how cattle genetic values can be estimated using basic genetic coding information [3].

Detecting genomic regions will help to identify potential candidate genes that may be responsible for genetic variation in MY and milk composition traits. These candidate genes could help to improve our understanding of the biological background of milk production traits. Genome-Wide Association Studies (GWAS) are a popular method for determining, which genes and gene regions influence the expression of specific phenotypes by identifying single nucleotide polymorphisms (SNPs) associated with the phenotypes across the whole genome [4, 5]. GWAS can effectively identify potential genetic variants associated with quantitative traits, and facilitate the utilization of molecular information for genomic selection in dairy cattle [6, 7].

GWAS have been extensively used in recent years to identify genomic regions and candidate genes for milk production traits in Holstein and its crossbreds in cattle populations from various countries. Numerous candidate genes and quantitative regions associated with milk production traits in Holstein and its crossbreds have already been identified [7–9, 16, 17]. The objective of this review was to summarize the findings of genomic regions and candidate genes associated with milk production traits including MY, FY, PY, FP, and PP in Holstein and its crossbreds.

2. Methods

Data were gathered from Google Scholar, Science Direct, PubMed, Springer Link, Web of Science, and Scopus using the keywords GWAS, genomic markers, Holstein, crossbred, and milk production traits. The current review included published studies that discussed candidate genes and genomic regions that were significantly associated with milk production traits in Holstein and its crossbreds. We included studies that used a P-value as a statistical significance criterion. In addition, we included studies that reported both SNPs and candidate genes. Similarly, only articles published in English in peer-reviewed journals since 2009 were included in this review. Thus, conference papers, books, book chapters, theses, and unpublished results were excluded from this review. To ensure consistency throughout the review, SNP names that differed from what researchers reported were converted to the rs name format.

3. GWAS for Milk Production Traits in Holstein and Its Crossbreds

The phenotypic expression of milk production traits (MY and milk composition) is controlled by many genes. The detection of potential candidate genes affecting milk production traits of cattle is made possible by the widespread availability of SNP markers through the fast-growing number of genotyped cattle [16]. Several GWAS focused on the identification of potential candidate genes and genomic regions underlying milk production traits (MY, FY, FP, PY, and PP). Most researchers conducted association studies using 50 K chips, except [7, 18]; who used 26 and 100 K chips, respectively. The methodologies they used were linear, single-locus, multi-locus, and Bayesian mixed models. This review summarized the 462 significantly associated SNPs from which 34 SNPs for milk production traits were repeatedly reported by various researchers at different rates. Ten SNPs were reported three and more than three from 34 SNPs: rs109421300, rs109350371, rs109146371, rs109558046, rs109752439, rs109234250, rs109968515, rs110199901, rs17870736, and rs43703011. While the ramming 24 SNPs were reported twice. For instance, rs109421300 was reported by [11, 13, 14, 17, 21].

Diacylglycerol O-acyltransferase 1 (DGAT1) was the most frequently reported candidate gene associated with one or more milk production traits by multiple authors [9, 11, 13, 14, 17, 19, 22]. GHR was reported by [11, 13, 21, 23]. MAPK15 was reported by [15, 21, 24]. KHDRBS3 was reported by [7, 16, 21]. The remaining candidate genes were reported by fewer than four researchers. Researchers [8, 16, 18] conducted association studies for milk production traits with crossbred dairy cattle ranging from 87.50% to <100% Holstein, Holsteinized Black-and-White Pied and Gir × Holstein (Girolando) in Thailand, Russia, and Brazil, respectively, using a single marker linear model. The remaining studies included in this review were conducted with Holstein and its crossbreds.

3.1. Milk Yield

MY is the most economically important trait, and several researchers were keenly interested in identifying the genes and genomic regions that contribute to its variation in Holstein and its crossbreds [7, 11, 13, 16, 17]. Several publications that utilized GWAS for the MY are shown in Table 1. These researchers reported 103 individual SNPs that were significantly associated with MY. These SNPs were found on all autosomal chromosomes except chromosomes 27 and 29 in Holsteins and their crossbreds. Figure 1 shows the frequency of SNPs identified by different researchers within each chromosome. Chromosomes 14 and 20 have a high number of SNPs. This information could be used to help focus research on these two chromosomes to improve MY.

Table 1.

Candidate genes and genomic regions for MY in Holstein and its crossbreds.

SNP name Gene Chromosome Breed Number of cattle Authors
rs41577598 BAIAP2 19 Canadian Holstein 462 [25]
rs41592943 GUCY2C 5
rs41608371 FBLN5 21
rs41632222 LOC512656 14
rs41633664 LOC785291 1
rs41643471 LOC508029 1
rs41655901 GALNT6 5
rs41656714 LOC407194 5
rs41658330 FANCC 8
rs43709850 LOC511740 3
rs42517915 LOC788012 9 Chinese Holstein 2,093 [21]
rs43030751 LOC100139865 9
rs41654691 INXA1 8 U.S. Holstein 1,654 [19]
rs42300745 TMX4 13
rs42586116 PTBP2 3
rs42586854 PTBP2 3
rs42725189 PTBP2 3
rs43408337 ULOC781500 4
rs109289569 L00531776 14
rs110384096 C-ICNG5 19
rs110944623 PIGN 24
rs41568120 PLCB1 13
rs41643761 SLC25A2 I 21
rs42914124 LOCI00140505 10
rs109104203 INO80 10 Portuguese Holstein 526 [24]
rs109832473 CACNB2 13
rs109942798 LOC525149 12
rs110323635 MAPK15 14
rs110476141 AQP4 24
rs41580384 CACNB2 13
rs41659095 GPAM 26
rs43186715 LOC525149 12
rs43272177 MARS 1
rs41640548 ATP11B 1 Chinese Holstein 445 [18]
rs110281536 EEF2K 25
rs41774442 GNA14 15 Thai Crossbreds 36 [8]
rs41776130 GNA14 15
rs41776828 LRRC4C 15
rs41779510 GNA14 15
rs41796094 GNA14 8
rs43705173 STAT1 2 Italian Holstein 45,115 [23]
rs41631082 ECI2 23 Russian Crossbreds 477 [9]
rs43364576 MACF1 3
rs109295123 SPOPL, HNMT 2
rs110748809 DTX1 17
rs110425841 PODXL2 22 Colombian Holstein 150 [10]
rs110718748 ANKS1B 5
rs41607880 TMEM229A 4
rs41913085 VIT 11
rs43483670 MAPK10 6
rs110482506 GHR 20 US Holstein 294,079 [26]
rs110527224 GC 6
rs137431035 PTGER4 20
rs41938455 C6 20
ss2019489562 UGDH 6
rs41613423 CYP7B1 14 Chinese Holstein 295 [11]
rs474736745 PAIP1 20 French Holstein 6321 [13]
rs109355809 U6 14 Brazilian Crossbreds 337 [16]
rs109381761 SLC51A 1
rs109704754 U6 18
rs110565520 CD47 1
rs41570140 FBXO11 11
rs41642215 BET1 4
rs41647684 BMPR1A 28
rs42123132 SSBP2 7
rs42215728 SLC24A2 8
rs42271 SLC24A2 8
rs42290054 CDH12 20
rs42490796 EDIL3 7
rs42583510 FBXO11 11
rs42900126 ANXA5 6
rs43424124 NUB1 4
rs108973652 IREB2 21
rs108977582 ITGB1BP1 11
rs108982955 TMEM247 11
rs109009656 MAP1B 20
rs109099963 FAM135B 14
rs109176086 KHDRBS3 14
rs109327460 SLC35B3 23
rs109840333 SLIT3 20
rs109854193 FST 20
rs109901641 FAM114A2 7
rs109912809 U6 7
rs109984167 HSPB3 20
rs110192732 HES1 1
rs29021936 ELAVL2 8
rs41657410 PAM 7
rs41919419 TANC2 19
rs42040508 MBP 24
rs42343030 GCNT2 23
rs42615382 TEX35 16
rs42674867 5S_rRNA 18
rs42934321 LAMA3 24
rs43419957 WDR86 4
rs110535430 MARCHF10 19
rs110632003 GRID2 6
rs110775601 NPFFR2 6 Korean Holstein 2780 [17]
rs135477609 ADRA1B 7
rs110527224 SLC4A4 6
rs517703887 PKHD1 23
rs524049037 GFRA2 8
rs108962265 PITRM1 1 Chinese Holstein 999 [7]
rs110246034 PRMT6 3
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Figure 1.

Figure 1

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The number of significant SNPs associated with MY found in chromosomes from Holstein and its crossbreds.

The candidate genes significantly affecting MY that were reported more than twice (Table 1) were GNA14 in Thai Holstein crossbreds [8], PTBP2 in U.S. Holstein [19], and U6 in Brazilian Holstein crossbreds [16].

3.2. Fat Yield and Fat Percentage

Fat is an important component of milk and it is controlled by gene networks associated with several metabolic and biological pathways. The identification of potential genes and their locations can provide valuable information that can be used for selective breeding to improve milk quality. A total of 46 significantly associated SNPs with FY and 117 significantly associated SNPs with FP were detected in various chromosomes from Holstein and its crossbreds. Several researchers [9, 12, 17, 19, 20] mentioned more than twice that two SNPs (rs109350371 and rs109421300) that were significantly associated with FP. Figure 2 shows the number of identified significant SNPs associated with FY and FP in chromosomes from Holstein and its crossbreds. Chromosome 14 contains a large number of significant SNPs associated with FP accounting for more than 75% of the SNPs on this chromosome. Conversely, for fat yield (FY), chromosomes 5 and 14 have an equal number of significantly associated SNPs.

Figure 2.

Figure 2

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The number of significant SNPs associated with FY and fat percentage (FP) in chromosomes from Holstein and its crossbreds.

A detailed list of the candidate genes, significant SNPs, and chromosome numbers for FY and FP is presented in Table 2. Several candidate genes influence the expression of FY, including inositol 1,4,5-trisphosphate receptor, type 2 (ITPR2), ATP-binding cassette sub-family C member 9 (ABCC9), sulfonylurea receptor 2 (SUR2), cleavage and polyadenylation specific factor 1 (CPSF1), DGAT1, phosphodiesterase 4B (PDE4), and methyl transferase like 15 (METTL15) reported by [7, 12, 13, 17, 25]. Similarly, multiple candidate genes influence the expression of FP, including 5-oxoprolinase, ATP-Hydrolysing (OPLAH), G protein-coupled receptor 20 (GPR20), collagen type XXII alpha 1 chain (COL22A1), glutamate receptor ionotropic NMDA type subunit associated protein (GRINA), forkhead box H1 (FOXH1), microsomal glutathione S-transferase 1 (MGST1), ephrin type-receptor A6 (EPHA6), and alanine and arginine rich domain containing protein (AARD) reported by [9, 11, 13, 15, 19, 21, 27].

Table 2.

Candidate genes and genomic regions for FY and FP in Holstein and its crossbreds.

SNP name Gene Chromosome Trait Breed Number of cattle Authors
rs29020642 LOC512171 1 FY Canadian Holstein 462 [25]
rs41634488 LOC786403 1
rs41637121 APP 1
rs41588659 COL1A2 4
rs41591894 ITPR2 5
rs41592942 GUCY2C 5
rs41652648 ITPR2 5
rs41653025 LOC540856 10
rs43703342 LOC514626 11
rs41645253 MGC139244 24
rs41569649 CAMK2G 28
rs41653440 PSAP 28 FY
rs41653491 LOC514949 28
rs43709929 LOC514870 3
rs29018853 LEC3 6
rs41592660 LOC616136 9
rs41657163 LOC535127 9
rs43710950 TPM1 10
rs41567322 TG 14
rs41579063 BIG1 14
rs41639879 LOC505156 17
rs41641678 LOC514186 21
rs41643783 MGC139789 21
rs41648176 LOC515764 26
rs29017368 LOC515967 5 FY Chinese Holstein 2,093 [21]
rs41648982 LOC511240 5
rs110090404 C14H8orf33 14
rs41664719 LOC516454 X
rs109948273 EIF2C2 1 FP
rs41617243 KBTBD10 2
rs41652649 ITPR2 5
rs43499009 NFIB 8
rs110704765 LOC526069 11
rs110710474 GFI1B 11
rs109436130 KHDRBS3 14
rs109529219 RHPN1 14
rs110143087 KCNK9 14
rs110293317 KHDRBS3 14
rs110323635 MAPK15 14
rs110411273 GPR20 14
rs110718625 KHDRBS3 14
rs111022074 LOC100138440 14
rs41567288 NIBP 14
rs41576704 EIF2C2 14
rs108995214 KHDRBS3 14
rs109118650 LOC618755 14
rs109225594 KCNK9 14
rs109230014 KCNK9 14
rs109241573 KHDRBS3 14
rs109402117 LOC618755 14
rs109476486 LYPD2 14
rs109617015 ZC3H3 14
rs109661298 EEF1D 14
rs109670279 PTK2 14
rs109742607 MAPK15 14
rs110057993 KHDRBS3 14
rs110165168 MIRN30D 14
rs110339989 OPLAH 14
rs110351374 COL22A1 14
rs110351748 COL22A1 14
rs110424520 GPR20 14
rs110501942 LOC618755 14
rs110502094 LOC100138440 14
rs110522477 KHDRBS3 14
rs110545496 KHDRBS3 14
rs110626984 CYP11B1 14
rs110775004 NIBP 14
rs110892754 LOC524939 14
rs111018678 NIBP 14
rs41576704 EIF2C2 14
rs41624797 PTK2 14
rs41627764 ZNF623 14
rs41630614 LOC785799 14
rs41657812 LOC100138440 14
rs42305942 LOC100138440 14
rs42310935 LOC100138440 14
rs55617160 NIBP 14
rs109950724 LOC782348 5 FY U.S. Holstein 1,654 [19]
rs110355546 ZBPI 13
rs41639184 LPP X
rs110267314 LM03 5 FP
rs41592948 GABARAPL1 5
rs109146371 FOXHI 14
rs109350371 LOC786966 14
rs109421300 DGAT1 14
rs109558046 VPS28 14
rs109752439 ZAT34 14
rs110017379 NIBP 14
rs110060785 GPITIBP1 14
rs110891564 KCNK9 14
rs110091513 SART3 17
rs109062793 AP1B4 X
rs109116007 SYTL5 X
rs41919985 FASN 19 FY Italian Holstein 800 [22]
rs41613079 EPHA7 9 FP Russian Holstein 61 [20]
rs42723319 EPHA7 9
rs109350371 LOC786966 14
rs109421300 DGAT1 14
rs134390757 LxR-α 15 FY Italian Holstein 45,115 [23]
rs135588030 ORL2 5 FP
rs43349286 LPAAT 23
rs41624917 PLCE1 26
rs41670205 LRP1B 2 FP Colombian Holstein 150 [10]
rs109245784 CLCN1 4
rs43655765 SNRNP200 11
rs110897514 PCDH18 17
rs41571534 WSCD1 19
rs41629750 GRINA 14 FP Russian Crossbreds 477 [9]
rs109350371 PLEC 14
rs109421300 DGAT1 14
rs109968515 CYHR1 14
rs110199901 ZNF696 14
rs17870736 VPS28 14
rs42406616 ABCC9 5 FY US Holstein 294,079 [26]
rs42718234 ABCC9 5
rs109350371 LOC786966 14
rs133114040 EPS8 5 FP
rs109146371 FOXH1 14 FP Chinese Holstein 295 [11]
rs109752439 C14H8orf33 14
rs208148726 AKT3 16
rs43526055 ADRA1B 7 FY Chinese Holstein 1220 [14]
rsl37676276 VIT 11
rs135780687 GRPR x
rsl09528658 EF400 17
rs42295213 EPHA6 1 FP
rs136949224 SCARA5 8
rs110825388 CPSF1/ADCK5 14 FY French Holstein 6321 [13]
rs211210569 MGST1 5
rs208248675 MGST1 5 FP
rs136548039 HERC5 6
rs109982707 PAEP 11
rs109234250 DGAT1 14
rs208675276 GPAT4 5′ UTR 27
rs110199901 LY6H 14 FY Chinese Holstein 300 [15]
rs109742607 MAPK15 14 FP
rs41624797 PTK2 14
Na rs LY6H 14
rs109476486 LYNX1 14
rs109617015 VAMP2 14
rs110339989 OPLAH 14
rs137787931 MROH1 14
rs17870736 VPS28 14
rs41627764 MIR193A-2 14
rs41630614 RPL8 14
rs41596885 PDE4B 3 FY Korean Holstein 2780 [17]
rs42314807 PDE4B 3
rs43454033 ANO2 5
rs109234250 DGAT1 14
rs109326954 DGAT1 14
rs109421300 DGAT1 14
rs110812136 SPATC1 14
rs135258919 HSF1 14
rs208317364 DGAT1 14
rs435871639 PKHD1 23
rs109414214 EXT1 14 FP Indian Crossbreds 96 [27]
rs109632163 NOV 14
rs41614632 - 14
rs41665025 SNTG1 14
rs41730911 FABP, PMP2 14
rs42485761 ZFPM2 14
rs43067787 KCNB2 14
rs108957364 AARD 14
rs110390518 - 14
rs110981268 SNX16 14
rs81118743 RF00026 14
rs43527533 TENM2 7 FY Chinese Holstein 999 [7]
rs42206791 METTL15 15
rs137260850 PLA2G4A 16
rs109656599 CDH13 18
rs109595510 RCSD1 3 FP
rs210744919 MGST1 5
rs133840542 SUPT2OH 12
rs137071126 SLC52A2 14
rs109278135 NOL4 24
rs133996308 PLAU 28
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3.3. Protein Yield and PP

Candidate genes, significant SNPs, and chromosome numbers for PY and PP are presented in Table 3. There were 44 significantly associated SNPs for PY and 101 significantly associated SNPs for PP in Holstein and its crossbreds. Figure 3 shows the number of significant SNPs associated with PY and PP in chromosomes from Holstein and its crossbreds. Many significant SNPs were reported on chromosome 20, and about half of the significant SNPs for PP were identified on chromosomes 20, 6, and 5. In addition, chromosomes 1 and 5 had a large number of significant SNPs for PY.

Table 3.

Candidate genes and genomic regions for PY and PP in Holstein and its crossbreds.

SNP name Gene Chromosome Trait Breed Number of cattle Authors
rs41591535 LOC781748 4 PY Canadian Holstein 462 [25]
rs29011990 MGC155155 8
rs41636749 LOC538513 18
rs41648723 CTBP2 26
rs41606880 JDP1 28
rs41650658 NRCAM 4 PP
rs29014633 CACNG2 5
rs41590827 RAC2 5
rs41593881 HIF1A 10
rs29021058 PLCG1 13
rs41566192 MGC127374 13
rs41637636 SLC38A3 22
rs29016156 LOC517805 23
rs109452554 ETS2 1 PY Chinese Holstein 2,093 [21]
rs109680710 DIP2A 1
rs41586699 PDE9A 1
rs109271556 LOC781902 3
rs109700191 SLC30A7 3
rs29025951 LOC100138725 3
rs41589462 LOC539739 3
rs110896997 PDHA2 6
rs41659807 LOC788115 9
rs109819417 NKAIN3 14
rs110618422 CSF2RB 5 PP
rs42552739 NCF4 5
rs81154068 HERC3 6
rs29018333 LOC536367 6
rs41622323 PKD2 6
rs43463988 LOC100140991 6
rs110805364 NIBP 14
Na rs GHR 20
rs109181046 GDNF 20
rs110679619 RICTOR 20
rs29013890 LOC782833 20
rs29014437 LOC782284 20
rs29018751 NIPBL 20
rs41574319 RAI14 20
rs41581059 LOC100138964 20
rs41937533 LOC518808 20
rs41941633 FYB 20
rs41941646 C9 20
rs41942492 NIPBL 20
rs41945918 LOC782462 20
rs42954630 NIPBL 20
rs109583255 CRABP1 21 PY U.S. Holstein 1,654 [19]
rs29011 699 ALDH5A1 23
rs110736402 L424P2 X
rs41598282 ATP1B4 X
rs110675489 SREBF2 5 PP
rs110931400 PDGFRA 6
rs111032162 PDGFRA 6
rs109024105 RPL37 9
rs109352200 USP 3 8 17
rs41256775 L0052 8054 17
rs109375227 Artora 18
rs109570377 CX036 X
rs108964624 LOC781178 X
rs110304690 COL4 X
rs110328561 LOC781178 X
rs41628209 LOC616260 X
rs42967999 LOC781902 3
rs41569048 PTHLH 5 PP Dutch Holstein 1,713 [28]
rs41640170 HEATR7B2 20
rs42529901 LOC788223 6 PY Portuguese Holstein 526 [24]
rs42749054 MAPK9 7
rs109593545 BRD7 18
rs41255191 OTUD7A 21
rs109826203 ACSM5 25
Na rs CSN3 6 PP Italian Holstein 800 [22]
rs109163366 PPARGC1A 6
rs110980619 HPS3 1 PY Russian Holstein 61 [20]
rs41647284 SLC16A7 5
rs41601570 ARL15 20 PP
rs109007595 POU1F2 1 PP Italian Holstein 45,115 [23]
No rs PPARGC1A 6
rs109579682 PPARGC1A 6
rs43703011 CSN3 6
rs43703017 CSN5 6
rs137457402 LPIN1 11
rs41255713 CCL3 19
rs109136815 GHR 20
rs29023352 INSIG1 4 PP Colombian Holstein 150 [10]
rs41624303 Arntl2 5
rs29014693 NMBR 9
rs41772701 CAPN5 15
rs110425841 PODXL2 22
rs41576177 OSBPL1A 24
rs109670279 BOD1L1 6 PP Russian Crossbreds 477 [9]
rs43592374 UBE3D 9
rs43710185 IL15 17
rs109774038 NDUFA9 5 PY US Holstein 294,079 [26]
rs132896414 GALNT8 5
rs379188781 CCND2 5
rs135228504 ZNF34 14
rs109558046 VPS13B 14 PP
rs110478571 NLK 19 PP Chinese Holstein 769 [12]
rs109558046 LOC104975266 20
rs110000229 GHR 20
rs41257416 HCN1 20
rs42418694 SND1 4 PY Chinese Holstein 295 [11]
rs41579063 ARFGEF1 14
rs41629750 SPATC1 1 PP
rs109748124 TNFSF10 1
rs41602511 YTHDF3 1
rs41617243 KLHL41 2
rs110256520 ATP1A1 3
rs110420888 ATP1A1 3
rs134541510 RPAP3 5
rs137408198 CD27 5
rs29015155 RPAP3 5
rs41592948 GABARAPL1 5
rs110672723 CSN2 6
rs110727998 GML 14
rs41579932 ARMC1 14
rs110834172 KSR2 17
rs29014438 SLC1A3 20
rs29021190 SLC1A3 20
rs41639260 GHR 20
rs41934711 CCNB1 20
rs134480235 SLCO1A2 5 PY Chinese Holstein 1220 [14]
rs109875012 ZNF384 5 PP
rs108996837 EXOC3L4 21
rs136903701 ABCC9 5 PY French Holstein 6321 [13]
rs43703011 CSN2 6
rs134511693 EFNA4 3 PP
rs456403270 TBC1D22A 5
rs383909572 HSTN 6
rs41622323 PKD2 6
rs135458711 SLC39A4 14
rs110144962 APOA4 15
rs208817293 WDR74/U2 29
rs378017490 PICALM 29
rs799074643 UMPS 1 PY Korean Holstein 2780 [17]
rs211419403 GFRA2 8
rs109957491 MFSD1 1 PY Chinese Holstein 999 [7]
rs109097262 PLCB4 13
rs41906111 MY01D 19
rs43496186 WNT9A 7 PP
rs109425744 CORO2B 10
rs135708753 ATP11A 12
rs132711282 FBX O 43 14
rs43002440 KHDRBS3 14
rs110387086 MLXIP 17
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Figure 3.

Figure 3

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The number of significant SNPs associated with PY and protein in chromosomes from Holstein and its crossbreds.

Table 3 shows potential genes, significant SNPs, and chromosomes associated with PY and PP. Genes associated with PY, included pyruvate dehydrogenase E1 subunit alpha 2 (PDHA2), C-terminal binding protein 2 (CTBP2), mitogen-activated protein kinase 9 (MAPK9), Hermansky-Pudlak syndrome-3 (HPS3), ADP ribosylation factor guanine nucleotide exchange factor 1 (ARFGEF), solute carrier organic anion transporter family member 1A2 (SLCO1A2), major facilitator superfamily domain containing 1 (MFSD1) [7, 14, 20, 21, 24, 25]. Findings indicate several potential genes associated with PP, for example, growth hormone receptor (GHR), nipped-B-like protein (NIPBL), platelet-derived growth factor receptor alpha (PDGFRA), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A), casein kappa (CSN3), RNA polymerase II associated protein 3 (RPAP3), solute carrier family 1 member 3 (SLC1A3), and zinc finger protein 384 (ZNF384) [7, 11, 14, 19, 22, 23].

3.4. All Milk Production Traits

A total of 136 SNPs were significantly associated with two or more milk production traits (MY, FY, PY, FP, and PP). According to Fontanesi et al. [22], rs109234250 was significantly associated with all milk production traits (MY, FY, PY, FP, and PP). As reported by [11, 12, 15, 17, 21, 22], 14 SNPs frequently affected four, 39 SNPs three, and 86 SNPs two of milk production traits. Number of significant SNPs associated with multiple milk production traits in Holstein and its crossbreds are shown in Figure 4. There was a greater number of SNPs frequently affected multiple milk production traits on chromosome 14. Thus, selection programs should focus on candidate genes and genomic regions that are known to influence multiple production traits.

Figure 4.

Figure 4

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The number of SNPs significantly associated with multiple milk production traits in Holstein and its crossbreds.

Candidate genes, significant SNPs, and chromosomes that are simultaneously associated with more than one milk production trait are listed in Table 4. Several promising candidate genes were identified, including DGAT1, PLEC, Rho GTPase activating protein 39 (ARHGAP39), protein phosphatase 1 regulatory subunit 16A (PPP1R16A), and sphingomyelin phosphatase 5 (SMPD5). Genes retinol saturase (RETSAT), AarF domain containing kinase 5 (ADCK5), arc regulates transcription adhesion G protein-coupled receptor B1 (ARC-ADGRB1), Rho GTPase activating protein 39 (ARHGAP39), DGAT1, forkhead box H1 (FOXH1), PLEC, solute carrier family 52 member 2 (SLC52A2), and prolactin receptor (PRLR) frequently affected four milk production traits [11, 12, 15, 21].

Table 4.

Candidate genes and genomic regions affecting multiple milk production traits in Holstein and its crossbreds.

SNP name Gene Chromosome Traits Breed Authors
rs41629125 ITGB5 1 MY, FY, and PY Canadian Holstein [25]
rs41631818 MGC128242 1 MY, FY, and PY
rs41587408 PDZK1 3 FP and PP
rs41578761 LOC529633 7 FY and PY
rs41662488 LOC785678 9 MY and PY
rs41569023 ROCK2 11 MY nad PY
rs41579049 5-OPase 14 FY and FP
rs41580517 KCNQ3 14 FY and FP
rs41587081 ZFHX4 14 MY and FP
rs41628862 BIG1 14 MY and PY
rs41633631 TG 14 MY and FP
rs41570561 SCARB1 17 FP and PP
rs41581694 FOXA3 18 MY and PY
rs41585246 SERPINA3-5 21 MY and PY
rs41644615 SERPINA5 21 MY, FY, and PY
rs41640789 POLR1C 23 FY and FP
rs41643632 LOC534225 23 MY and PY
rs43282015 LOC614166 1 MY and PY Chinese Holstein [21]
rs41663626 LOC534011 3 MY and PY
No rs HAL 5 MY and PY
rs110727998 GML 14 MY and FP
No rs COL22A1 14 MY and PY
rs109146371 FOXH1 14 MY, FY, and PP
rs109350371 LOC786966 14 MY, FY, PY, and PP
rs109421300 DGAT1 14 MY, FY, and PP
rs109752439 C14H8orf33 14 MY and PY
rs109968515 CYHR1 14 MY, FY, and PP
rs110017379 NIBP 14 MY, PY, and FP
rs110060785 GPIHBP1 14 MY, PY, and FP
rs110199901 ZNF66 14 MY and FP
rs110622450 COL22A1 14 MY and FP
rs17870736 VPS28 14 MY, FY, and PP
rs41256919 MAF1 14 MY and FP
rs41629750 GRINA 14 MY, FP, and PP
rs41583200 C26H10orf84 26 MY and PY
rs42462826 FKBP2 1 FY and PY U.S. Holstein [19]
rs109250591 ITC14 1 FY and PY
rs109703572 9 MY and FY
rs43101493 GNAS 13 MY, FY, and PY
rs41585412 GNAS 13 MY, FY, and PY
rs41630667 GNAS 13 MY, FY, and PY
rs111018678 NIBP 14 FP and PP
rs42422883 HHIP 17 FY and PY
rs108993234 PGLYRPI 18 MY, FY, and PY
rs29010796 MAF 18 FY and PY
rs109343058 GPRI 10 23 FY and PY
rs110886345 26 FY, PY, and PP
rs110898125 26 FP and PP
rs41626960 MGMT 26 FY and PY
rs42227052 FUT10 27 MY, FY, and PY
rs41575183 27 FY and PY
rs109335394 X FY and PY
rs41579345 GLRA2 X FY and PY
rs41628209 LOC616260 X FY and PY
rs41255709 CXCR1 2 MY, FY, and PY Italian Holstein [22]
rs29004485 LEP 4 MY, FY, and PY
rs29004488 LEP 4 MY, FY, and PY
rs109299401 CSN3 6 PY and PP
rs133669403 PPARGC1A 6 MY and PY
rs43703011 CSN2 6 MY and PY
rs109625649 LGB 11 MY and PY
rs110066229 LGB 11 MY and PY
rs41255679 LGB 11 MY and PY
No rs CRH 14 PY and PP
rs109162116 DGAT1 14 MY, FY, PY, and FP
rs109234250 DGAT1 14 MY, FY, PY, FP, and PP
rs41580467 TG 14 MY and FP
rs41758918 TPH1 15 MY and PY
rs42321611 PRLR 20 MY, FY, PY, and PP
rs42714482 THRSP 29 MY, FY, and PY
rs29017970 LOC104973750 13 MY and PY Russian Holstein [20]
rs41850250 TRAFD1 17 MY and PY
rs135514413 ETS2 1 FP and PP Italian Holstein [23]
rs41608610 DGKG 1 MY, FP, and PP
rs109299401 CSN2 6 PY and PP
rs110981354 CSN1S1 6 FY, FP, and PP
rs133669403 PPARGC1A 6 MY, FP, and PP
rs43703013 CSN4 6 MY and PP
rs43703015 CSN4 6 MY, FY, and PY
rs43706475 CSN3 6 MY and PY
rs110590698 LPL 8 FY, FP, and PP
rs8193666 TLR4 8 MY, FP, and PP
rs110757796 FABP4 14 MY and PY
rs110937773 FGF2 17 MY and FY
rs109578101 STAT5A 19 MY, PY, and FP
rs109686238 CCL3 19 FY and PY
rs109428015 PRLR 20 FP and PP
rs41923484 GHR 20 PY, FP, and PP
rs41257077 PI 21 FY and PY
rs43765462 LTF 22 FY and FP
rs43706495 BTN1A1 23 MY and FP
rs109913786 AGPAT6 27 FY and FP
rs381714237 FCGR2B 3 MY, PY, and PP US Holstein [26]
rs110825637 MGST1 5 FY and FP Chinese Holstein [12]
rs137735153 PLEKHA5 5 FY and FP
rs109901151 SLC4A4 6 MY and PY
rs110694875 ADAMTS3 6 MY and PY
rs136639319 TBC1D1 6 FP and PP
rs137147462 GC 6 MY and PY
rs378415122 CENPE 6 MY, FY, and PY
rs385060942 CENPE 6 MY, FY, and PY
rs453960300 CENPE 6 MY, FY, and PY
ss2137349051 CENPE 6 MY, FY, and PY
ss2137349053 CENPE 6 MY, FY, and PY
rs377943075 ACSBG2 7 FY and PP
rs134985825 RETSAT 11 MY, FY, PY, and PP
rs109146371 PPP1R16A 14 MY, FY, PY, and PP
rs109350371 PLEC 14 MY, FY, PY, and PP
rs109558046 ARC-ADGRB1 14 MY, FY, PY, and FP
rs110914335 LY6H (d) 14 MY and PY
rs134444531 NLK 19 PY and PP
rs41573457 MRPS30 20 MY and PP
ss2137349058 MAP3K1 20 MY, FY, and PY
rs41589462 KCND3 3 FP and PP Chinese Holstein [11]
rs136195618 PROP1 7 MY and PY
rs109350371 PLEC 14 MY, PY, FP, and PP
rs109421300 DGAT1 14 MY, FP, and PP
rs109968515 CYHR1 14 FY and PY
rs110017379 TRAPPC9 14 MY, FP, and PP
rs41579243 FAM135B 14 FP and PP
rs109646517 MTMR3 17 MY and PY
rs29014437 SLC1A3 20 MY and PP
rs41580312 OSMR 20 MY and PP
rs41942492 NIPBL 20 FP and PP
rs42340412 ARID5B 28 FP and PP
rs109421300 DGAT1 14 FP and PP Chinese Holstein [14]
rs109007040 VPS13B 14 MY, FP, and PP French Holstein [13]
rs109421300 DGAT1 14 MY and PY
rs41921161 CCDC57 19 FY and FP
rs110231369 ARHGEF28 20 FY and PY
rs385640152 GHR 20 FP and PP
No rs ADCK5 14 MY, FY, FP, and PP Chinese Holstein [15]
No rs FOXH1 14 MY, FY, FP, and PP
No rs GRINA 14 FY, FP, and PP
No rs SLC52A2 14 MY, FY, FP, and PP
rs109146371 FOXH1 14 MY, FY, FP, and PP
rs109752439 C14H8orf33 14 FY and FP
rs110323635 MAPK15 14 FY and FP
rs721532493 PALLD 8 MY, FY, and PY Korean Holsteins [17]
rs109421300 DGAT1 14 MY, FY, PY, and PP
rs135549651 SMPD5 14 MY, FY, PY, and PP
rs207655744 HSF1 14 MY and FY
rs208640292 HSF1 14 MY and FY
rs209876151 DGAT1 14 MY and FY
rs211016627 HSF1 14 MY and FY
rs211223469 DGAT1 14 MY and FY
rs211282745 HSF1 14 MY and FY
rs384957047 DGAT1 14 MY and FY
rs380223715 PKHD1 23 MY and PY
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4. Conclusion

This review summarized information on identified candidate genes and genomic regions associated with milk production traits in Holstein and its crossbreds from various regions of the world. Most of the identified SNPs and candidate genes were on chromosome 14. One of the challenges in dairy cattle selection is that milk production traits are expressed after the first calving. Candidate gene and genomic region information would permit earlier selection of males and females, shorten the generation interval, and accelerate genetic progress for milk production traits.

Conflicts of Interest

The author(s) declare(s) that they have no conflicts of interest.

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